Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer

ABSTRACT

There is provided compounds of formula I (I) or pharmaceutically-acceptable salts thereof, wherein L, R1, R2, R3 and X have meanings provided in the description, which compounds are useful in the treatment of cancers.

FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions, andtheir use in the treatment of cancer. In particular, the inventionrelates to novel compounds, compositions and methods for the treatmentof cancers through specific and potent inhibition of thioredoxinreductase with minimal inhibition of glutathione reductase.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Although the increased understanding of the role of oncogenes, and thedevelopment of new anticancer treatments and diagnosis, have improvedthe life expectancy of cancer patients, there is still a high medicalneed to find more effective and less toxic treatments for cancers, suchas breast cancer, head and neck cancer, melanoma, glioblastoma,leukaemia, and colon and lung cancer.

It is well known that excessive production of reactive oxygen species isa common feature of cancer cells due to their distorted metabolism andexaggerated replicative drive. Cancer cells are able to survive theirunnaturally high production of reactive oxygen species throughconcomitant upregulation of robust antioxidant defence mechanisms.

Radiotherapy and chemotherapy protocols compete against antioxidantdefence mechanisms, further increasing reactive oxygen species levelsbeyond adapted thresholds through targeting of multiple cellularcompartments and targets. Thus, sensitization of cancer cells to theirendogenous reactive oxygen species production can additionally inducecancer cell death. In contrast, normal cells have reserved capacity tocombat oxidative stress. With this in mind, it has been suggested thatif reactive oxygen species levels could be further increased, or thecellular defences against reactive oxygen species could be deliberatelyimpaired, these systems may serve to allow for a possible therapeuticmechanism of action for anticancer therapy (Luo, J., Solimini, N. L. &Elledge, S. J., Cell, 136, 823 (2009); Trachootham, D., Alexandre, J. &Huang, P., Nat Rev Drug Discov, 8, 579 (2009)).

Increased tolerance to oxidative stress of cancer cells can occurthrough activation of the two major antioxidant systems in human andother mammals: the glutathione and thioredoxin systems. Concomitantinhibition of the glutathione and thioredoxin systems therefore has beenproposed as a mechanism for anticancer activity (Harris, I. S., et al.,Cancer Cell 27, 211 (2015); Mandal, P. K., et al., Cancer Res, 70,9505-9514 (2010); Fath, M. A., Ahmad, I. M., Smith, C. J., Spence, J. &Spitz, D. R., Clin Cancer Res., 17, 6206 (2011)).

Cytosolic thioredoxin reductase is a key enzyme for the whole cytosolicthioredoxin system, which in turn is responsible for a cascade ofsignalling events and antioxidant activities (Amér, E. S. J., BiochimBiophys Acta, 1790, 495-526 (2009)). A high expression level ofcytosolic thioredoxin reductase in various cancers correlates to a moresevere cancer phenotype, chemotherapeutic drug resistance, and poorprognosis.

However, as normal, non-cancerous cells require either the glutathioneor the thioredoxin systems for survival (Amér, E. S. & Holmgren, A., EurJ Biochem, 267, 6102 (2000); Lillig, C. H., Berndt, C. & Holmgren, A.,Biochim Biophys Acta, 1780, 1304 (2008); Prigge, J. R., et al., FreeRadic Biol Med, 52, 803 (2012)), it is difficult to therapeuticallytarget both of these antioxidant systems without triggering majorunwanted toxicities.

It has been suggested that several chemotherapeutic protocols foranticancer treatment involve inhibition of cytosolic thioredoxinreductase together with other components of the cell (Becker, K. et al.Eur. J. Biochem., 267, 6118 (2000)). For example, motexafin gadolinium,marketed as a radiosensitizing drug and thioredoxin reductase inhibitor,is also a potent ribonucleotide reductase inhibitor (Hashemy, S. I.,Ungerstedt, J. S., Zahedi Avval, F. & Holmgren, A., J Biol Chem, 281,10691 (2006)). Auranofin, a potent thioredoxin reductase inhibitor,concomitantly localizes to and damages the mitochondria (Cox, A. G.,Brown, K. K., Amér, E. S. & Hampton, M. B., Biochem Pharmacol, 76,1097-1109 (2008); Krishnamurthy, D., et al., J Med Chem, 51, 4790(2008); Rigobello, M. P., Folda, A., Baldoin, M. C., Scutari, G. &Bindoli, A., Free Radic Res, 39, 687 (2005)).

The structure and function of thioredoxin reductase, biological effectsassociated with its inhibition, such as in its potential as a mechanismfor cancer treatment, and compounds previously disclosed as potentialinhibitors are reviewed in Zhang, B. et al., Expert Opinion onTherapeutic Patents (2016).

The present innovation relates to the development and usage of novelcompounds specifically and potently targeting cytosolic thioredoxinreductase, without targeting the closely related flavoproteinglutathione reductase that supports the function of the glutathionesystem, as a means of obtaining a new efficient anticancer treatmentthat at the same time presents limited toxic side effects.

In particular, the inventors have unexpectedly found that novel,pyridinyl sulfone compounds may achieve highly selective inhibition ofcytosolic thioredoxin reductase by acting as strongly-binding (and, insome cases, effectively irreversible) inhibitors of the enzyme withoutcausing significant inhibition of glutathione reductase.

Specifically, by potently inhibiting thioredoxin reductase selectivelyover glutathione reductase, the novel pyridinyl sulfones have thepotential to be effective against cancer forms having dysfunctionalredox status, with minimal general toxic effects to normal cells. Suchinhibitors may also be a suitable adjuvant therapy to be used inconjunction with radiotherapies or other chemotherapeutic approaches.Based on these surprising results, the present invention aims to providenew treatments for cancers.

Certain alkylsulfonyl-nitropyridines have been synthesized or allegedcommercially available but with no use ascribed to them, as describedin: Talik, Z., et al., Prace Naukowe Akademii Ekonomicznej imieniaOskara Langego we Wroclawiu 255, 137 (1984); Talik, T.; Talik, Z., Pol.J. Chem., 52, 163 (1978) and Moshchitskii, S. D., et al., Khim. Get.Soedin., 802 (1975).

International patent application WO 03/093250 claims e.g.6-methoxy-2-(methylsulfonyl)-3-nitropyridine as an intermediate for thesynthesis of compounds used for CNS related disorders.

European patent application EP 220857 claims e.g.6-(isobutylsulfonyl)-5-nitropyridin-2-yl methanesulfonate and its use asan insecticide, acaricide and nematocide.

Jamoulle, J. C., et al., Ann. Pharm. Fr. 41, 61 (1983) describes certainalkylsulfonyl-nitropyridines as parasiticidals.

Certain alkylsulfonyl-nitropyridines are mentioned in Jamoulle, J. C.;Lapiere, C. L., J. Pharm. Belg. 30, 114 (1975).

US patent application 4456469 and European patent application EP 35893describe certain alkylsulfonyl-nitropyridines as herbicides.

International patent application WO 2015/081813 and Chinese patentapplications CN 105503827, CN 105085483, CN 104987324 and CN 10467221describe compounds useful in the treatment of cancer where certainnitropyridines substituted with an alkylsulfonyl group have been used assynthetic intermediates.

International patent application WO 97/08147 and German patentapplication DE 19531348 describe certain alkylsulfonylnitropyridines asfungicides for agricultural use.

International patent application WO 99/36391 describes twobenzenesulfonamides as therapeutic agents. Neither contains a pyridinering having a nitro substituent.

International patent application WO 2007/124546 describes3-cyano-4,6-diarylsubstituted pyridines useful for the treatment ofviral infections. However, none of the exemplified compounds contain anitro substituted pyridine linked via a sulfonyl moiety to an optionallysubstituted alkyl group.

International patent application WO 95/29897 describes certain (H⁺/K⁺)ATPase inhibitors and their use in treating viral infections. However,none of the exemplified compounds contain a nitro substituted pyridinelinked via a sulfonyl moiety to an optionally substituted alkyl group.

International patent application WO 98/54139 describes a process for thepreparation of pyridines linked to, for example, a propyl group via asulfonyl group. However, none of the exemplified compounds contain anitro substituted pyridine linked via a sulfonyl moiety to an optionallysubstituted alkyl group.

International patent applications WO 99/010320 and WO 99/017777 describecertain compounds and their use in treating conditions such as cancer.However, none of the exemplified compounds contain a nitro substitutedpyridine linked via a sulfonyl moiety to an optionally substituted alkylgroup.

International patent application WO 01/064642 describes certaincompounds and their use in treating coagulation disorders. However, noneof the exemplified compounds contain a nitro substituted pyridine linkedvia a sulfonyl moiety to an optionally substituted alkyl group.

Chinese patent application CN 102206172 describes certain antiviralcompounds. However, none of the exemplified compounds contain a nitrosubstituted pyridine linked via a sulfonyl moiety to an optionallysubstituted alkyl group.

International patent application WO 2007/076875 describes compoundsacting on the serotonin transporter. However, none of the exemplifiedcompounds contain a nitro substituted pyridine linked via a sulfonylmoiety to an optionally substituted alkyl group.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that certain nitro substituted pyridines linkedvia a sulfonyl moiety to an optionally substituted alkyl, alkenyl oralkynyl group have surprising properties which render such compoundsuseful in the treatment of cancers.

Compounds of the Invention

In a first aspect of the invention, there is provided a compound offormula I

-   or a pharmaceutically acceptable salt thereof, wherein:-   L represents —S(O)_(n)—;-   n represents 2 or 1;-   X represents C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or C₂₋₁₂ alkynyl each    optionally substituted by one or more groups independently selected    from Y;-   R¹ represents halo, —N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1);-   R² and R³ each independently represent H, halo, R^(a1), —CN,    -A^(a1)-C(Q^(a1))R^(b1), -A^(b1)-C(Q^(b1))N(R^(c1))R^(d1),    -A^(c1)-C(Q^(c1))OR^(e1), -A^(d1)-S(O)_(p)R^(f1),    -A^(e1)-S(O)_(p)N(R^(g1))R^(h1), -A^(f1-)-S(O)_(p)OR^(i1), —N₃,    —N(R^(j1))R^(k1), —N(H)CN, —NO₂, —ONO₂, —OR^(l1) or —SR^(m1),-   each A^(a1) to A^(f1) independently represents a single bond,    —N(R^(p1))— or —O—;-   each Q^(a1) to Q^(c1) independently represents ═O, ═S, ═NR^(a1) or    ═N(OR^(o1));-   each R^(a1) and R^(f1) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl each optionally substituted by one or more    groups independently selected from G^(1a), heterocyclyl optionally    substituted by one or more groups independently selected from    G^(1b), aryl optionally substituted by one or more groups    independently selected from G^(1c), or heteroaryl optionally    substituted by one or more groups independently selected from    G^(1d);-   each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1), R^(j1),    R^(k1), R^(l1), R^(m1), R^(n1), R^(o1) and R^(p1) independently    represents H, C¹⁻⁶ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each    optionally substituted by one or more groups independently selected    from G^(1a), heterocyclyl optionally substituted by one or more    groups independently selected from G^(1b), aryl optionally    substituted by one or more groups independently selected from    G^(1c), or heteroaryl optionally substituted by one or more groups    independently selected from G^(1d);-   any of R^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    G^(1b), C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl each optionally    substituted by one or more G^(1a), and ═O;    -   each G^(1a) and G^(1b) independently represents halo, —CN,        —N(R^(a2))R^(b2), —OR^(c2), —SR^(d2) or ═O;-   each R^(a2), R^(b2), R^(C2) and R^(d2) independently represents H,    or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally    substituted by one or more fluoro; or-   R^(a2) and R^(b2) are linked together to form, along with the    nitrogen atom to which they are attached, a 3- to 6-membered ring,    which ring optionally contains one further heteroatom and which ring    optionally is substituted by one or more groups independently    selected from fluoro and C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl    each optionally substituted by one or more fluoro;-   each Y independently represents halo, R^(a3), —CN,    -A^(a2)-C(Q^(a2))R^(b3), -A^(b2)-C(Q^(b2))N(R^(c3))R^(d3),    -A^(c2)-(Q^(c2))OR^(e3), -A^(d2)-S(O)_(q)R^(f3),    -A^(e2)-S(O)_(q)N(R^(g3))R^(h3), -A^(f2)-S(O)_(q)OR^(i3), —N₃,    —N(R^(j3))R^(k3), —N(H)CN, —NO₂, —ONO₂, —OR^(l3), —SR^(m2) or ═O;-   each Q^(a2) to Q^(c2) independently represents ═O, ═S, ═NR^(a3) or    ═N(OR^(o3));-   each A^(a2) to A^(f2) independently represents a single bond,    —N(R^(p3))— or —O—;-   each R^(a1) independently represents heterocyclyl optionally    substituted by one or more groups independently selected from    G^(2b), aryl optionally substituted by one or more groups    independently selected from G^(2c), or heteroaryl optionally    substituted by one or more groups independently selected from    G^(2d);-   each R^(f3) independently represents C₁₋₆ alkyl optionally    substituted by one or more groups independently selected from    G^(2a), heterocyclyl optionally substituted by one or more groups    independently selected from G^(2b), aryl optionally substituted by    one or more groups independently selected from G^(2c), or heteroaryl    optionally substituted by one or more groups independently selected    from G^(2d);-   each R^(b3), R^(c3), R^(d3), R^(e3), R^(g3), R^(h3), R^(i3), R^(j3),    R^(k3), R^(l3), R^(m3), R^(n3), R^(o3) and R^(p3) independently    represents H, C₁₋₆ alkyl optionally substituted by one or more    groups independently selected from G^(2a), heterocyclyl optionally    substituted by one or more groups independently selected from    G^(2b), aryl optionally substituted by one or more groups    independently selected from G^(2c), or heteroaryl optionally    substituted by one or more groups independently selected from    G^(2d); or-   any two R^(c3) and R^(d3), R^(g3) and R^(h3) and/or R^(j3) and    R^(k3) are linked together to form, along with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    heterocyclyl optionally substituted by one or more groups    independently selected from G^(2b), aryl optionally substituted by    one or more groups independently selected from G^(2c), or heteroaryl    optionally substituted by one or more groups independently selected    from G^(2d), and ═O;    -   each G^(2a) independently represents halo, —CN,        —N(R^(j4))R^(k4); —OR^(l4); —SR^(m4) or ═O;    -   each G^(2b) independently represents halo, R^(a4), —CN,        —N(R^(j4))R^(k4); —OR^(l4); —SR^(m4) or ═O;    -   each G^(2c) and G^(2d) independently represents halo, R^(a4),        —CN, -A^(a3)-(Q^(a4))R^(b4), -A^(b3)-C(Q^(b3))N(R^(c4))R^(d4),        -A^(c3)-C(Q^(c3))OR^(e4), -A^(d3)-S(O)_(q)R^(f4),        -A^(e3)-S(O)_(q)N(R^(g4))R^(h4), -A^(f3)-S(O)_(q)OR^(i4), —N₃,        —N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂, —OR^(l4) or —SR^(m4);    -   each Q^(a3) to Q^(c3) independently represents ═O, ═S, ═NR^(n4)        or ═N(OR^(o4));    -   each A^(a3) to A^(f3) independently represents a single bond,        —N(R^(p4))— or —O—;    -   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl        optionally substituted by one or more groups independently        selected from G^(3a), heterocyclyl optionally substituted by one        or more groups independently selected from G^(3b), aryl        optionally substituted by one or more groups independently        selected from G^(3c), or heteroaryl optionally substituted by        one or more groups independently selected from G^(3d);    -   each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(i4),        R^(k4), R^(l4), R^(m4), R^(n4), R^(o4) and —R^(p4) independently        represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each        optionally substituted by one or more groups independently        selected from G^(3a) or heterocyclyl optionally substituted by        one or more groups independently selected from G^(3b), aryl        optionally substituted by one or more groups independently        selected from G^(3c), or heteroaryl optionally substituted by        one or more groups independently selected from G^(3d); or-   any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(j4) and R^(k4)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected Gab;-   each G^(3a) and G^(3b) independently represents halo, R^(a5), —CN,    —N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O;-   each R^(a5) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl each optionally substituted by one or more groups    independently selected from G⁴;-   each R^(b5), R^(c5), R^(d5) and Res independently represents H, or    C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted    by one or more groups independently selected from G⁴; or-   each R^(b5) and R^(c5) are linked together to form, together with    the nitrogen atom to which they are attached, a 3- to 6-membered    ring, which ring optionally contains one further heteroatom and    which ring optionally is substituted by one or more groups    independently selected from G⁴;-   each G⁴ independently represents halo, R^(a6), —CN,    —N(R^(b6))R^(c6), —OR^(d6) or ═O;-   each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl each optionally substituted by one or more fluoro;-   each R^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by    one or more fluoro; and-   each p and q independently represents 1 or 2,-   which compounds may be referred to herein as compounds of the    invention,-   but with the provisos that the compound of formula I does not    represent:

(A)

-   2-((1-chloropropan-2-yl)sulfonyl)-6-methoxy-3-nitropyridine,-   2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethane-1-sulfonamide,-   2-((2-chloroethyl)sulfonyl)-6-methoxy-3-nitropyridine,-   2-((4-chlorobutan-2-yl)sulfonyl)-6-methoxy-3-nitropyridine,-   2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethane-1-sulfonyl    chloride,-   24(3-chloro-2-methylpropyl)sulfonyl)-6-methoxy-3-nitropyridine,-   2-((3-chloropropyl)sulfonyl)-6-methoxy-3-nitropyridine,-   6-methoxy-3-nitro-2-(vinylsulfonyl)pyridine,-   6-methoxy-2-(methylsulfonyl)-3-nitropyridine,-   6-(2,6-dichloro-4-(trifluoromethyl)phenoxy)-2-(methylsulfonyl)-3-nitropyridine,-   6-(2,6-dichloro-4-(trifluoromethoxy)phenoxy)-2-(methylsulfonyl)-3-nitropyridine,    or-   6-(2,6-dichloro-4-(trifluoromethyl)phenoxy)-2-(ethylsulfonyl)-3-nitropyridine;-   or

(B)

-   2-(butylsulfinyl)-3-nitro-pyridine;

or

(C)

-   3-[(3-nitro-2-pyridinyl)sulfinyl]-2-propenoic acid methyl ester,-   3-[(3-nitro-2-pyridinyl)sulfinyl]-2-propenoic acid ethyl ester,-   6-[(2-methylpropyl)sulfinyl]-5-nitro-2-methanesulfonate-2-pyridinol,-   3-chloro-2-[(6-chloro-3-nitro-2-pyridinyl)sulfinyl]-benzoic acid    ethyl ester,-   3-nitro-2-[(4-piperidinylmethyl)sulfinyl]-pyridine,-   3-nitro-2-[(3-pyrrolidinylmethyl)sulfinyl]-pyridine,-   3-nitro-2-[(3-piperidinylmethyl)sulfinyl]-pyridine,-   3-nitro-2-[(2-pyrrolidinylmethyl)sulfinyl]-pyridine,-   3-nitro-2-[(2-piperidinylmethyl)sulfinyl]-pyridine,-   4-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic    acid 1,1-dimethylethyl ester,-   3-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic    acid 1,1-dimethylethyl ester,-   3-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-pyrrolidinecarboxylic    acid, 1,1-dimethylethyl ester,-   2-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-pyrrolidinecarboxylic    acid 1,1-dimethylethyl ester,-   2-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic    acid 1,1-dimethylethyl ester,-   6-[2,6-dichloro-4-(trifluoromethoxy)phenoxy]-2-(methylsulfinyl)-3-nitro-pyridine,    or-   6-[2,6-dichloro-4-(trifluoromethyl)phenoxy]-2-(ethylsulfinyl)-3-nitro-pyridine.

For the avoidance of doubt, compounds of formula I and pharmaceuticallyacceptable salts thereof, not including the provisos, may be referred toherein as compounds of the invention. Similarly, references to compoundsof the first aspect of the invention will refer to compounds of formulaI as defined in the first aspect of the invention, including theprovisos, and pharmaceutically acceptable salts thereof. As such,compounds of the first aspect of the invention represent a particularembodiment of compounds of the invention.

The skilled person will understand that references herein to compoundsof the invention will include references to all embodiments andparticular forms thereof.

Unless indicated otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention pertains.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound ofthe invention with one or more equivalents of an appropriate acid orbase, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound ofthe invention in the form of a salt with another counter-ion, forexample using a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include carboxylatesalts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate,heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate,propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate,α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate,phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts),halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts(e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate,xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1- or 2-naphthalene-sulfonate or1,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, andthe like.

Particular base addition salts that may be mentioned include saltsformed with alkali metals (such as Na and K salts), alkaline earthmetals (such as Mg and Ca salts), organic bases (such as ethanolamine,diethanolamine, triethanolamine, tromethamine and lysine) and inorganicbases (such as ammonia and aluminium hydroxide). More particularly, baseaddition salts that may be mentioned include Mg, Ca and, mostparticularly, K and Na salts.

For the avoidance of doubt, compounds of the invention may exist assolids, and thus the scope of the invention includes all amorphous,crystalline and part crystalline forms thereof, and may also exist asoils. Where compounds of the invention exist in crystalline and partcrystalline forms, such forms may include solvates, which are includedin the scope of the invention. Compounds of the invention may also existin solution.

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution); for example, with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

As used herein, references to halo and/or halogen will independentlyrefer to fluoro, chloro, bromo and iodo (for example, fluoro andchloro).

Unless otherwise specified, C_(1-z) alkyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-z)cycloalkyl group). When there is a sufficient number (i.e. a minimum offour) of carbon atoms, such groups may also be part cyclic (so forming aC_(3-z) partial cycloalkyl group). Part cyclic alkyl groups that may bementioned include cyclopropylmethyl and cyclohexylethyl. When there is asufficient number of carbon atoms, such groups may also be multicyclic(e.g. bicyclic or tricyclic) or spirocyclic.

Unless otherwise specified, C_(2-z) alkenyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of three) of carbon atoms, bebranched-chain, and/or cyclic (so forming a C_(4-z) cycloalkenyl group).When there is a sufficient number (i.e. a minimum of five) of carbonatoms, such groups may also be part cyclic. Part cyclic alkenyl groupsthat may be mentioned include cyclopentenylmethyl andcyclohexenylmethyl. When there is a sufficient number of carbon atoms,such groups may also be multicyclic (e.g. bicyclic or tricyclic) orspirocyclic.

Unless otherwise specified, C_(2-z) alkynyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of four) of carbon atoms, bebranched-chain.

For the avoidance of doubt, the skilled person will understand that theterm alkyl will refer to saturated hydrocarbon moieties, whereas theterm alkenyl will refer to unsaturated hydrocarbon moieties containingat least one carbon-carbon double bond and the term alkynyl will referto unsaturated hydrocarbon moieties containing at least onecarbon-carbon triple bond, which alkyl, alkenyl and alkynyl groups maybe referred to collectively as hydrocarbyl groups. Further, suchunsaturated hydrocarbon moieties will be referred to by reference to thehighest degree of unsaturation comprised therein (e.g. a hydrocarbonmoiety comprising at least one carbon-carbon double bond and at leastone carbon-carbon triple bond will be referred to as alkynyl, althoughsuch moieties may also be referred to using terms such as “alkenylalkynyl” and the like).

As used herein, the term heterocyclyl may refer to non-aromaticmonocyclic and bicyclic heterocyclyl groups (which groups may further bebridged) in which at least one (e.g. one to four) of the atoms in thering system is other than carbon (i.e. a heteroatom), and in which thetotal number of atoms in the ring system is between three and twelve(e.g. between five and ten and, most preferably, between three andeight, e.g. a 5- or 6-membered heterocyclyl group). Further, suchheterocyclyl groups may be saturated, forming a heterocycloalkyl, orunsaturated containing one or more carbon-carbon or, where possible,carbon-heteroatom or heteroatom-heteroatom double and/or triple bonds,forming for example a C_(2-z) (e.g. C_(4-z)) heterocycloalkenyl (where zis the upper limit of the range) or a C_(7-z) heterocycloalkynyl group.C_(2-z) heterocyclyl groups that may be mentioned include7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl,azetidinyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl,dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl),dithianyl (including 1,4-dithianyl), dithiolanyl (including1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl,morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl,oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridinyl(such as 1,2,3,4-tetrahydropyridinyl and 1,2,3,6-tetrahydropyridinyl),thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl,trithianyl (including 1,3,5-trithianyl), tropanyl and the like.Substituents on heterocyclyl groups may, where appropriate, be locatedon any atom in the ring system including a heteroatom. Further, in thecase where the substituent is another cyclic compound, then the cycliccompound may be attached through a single atom on the heterocyclylgroup, forming a so-called “spiro”-compound. The point of attachment ofheterocyclyl groups may be via any atom in the ring system including(where appropriate) a further heteroatom (such as a nitrogen atom), oran atom on any fused carbocyclic ring that may be present as part of thering system. Heterocyclyl groups may also be in the N- or S-oxidisedform.

At each occurrence when mentioned herein, particular heterocyclyl groupsthat may be mentioned include 3- to 8-membered heterocyclyl groups (e.g.a 4- to 6-membered heterocyclyl group).

As may be used herein, the term aryl includes references to C₆₋₁₄ (e.g.C₆₋₁₀) aromatic groups. Such groups may be monocyclic or bicyclic and,when bicyclic, be either wholly or partly aromatic. C₆₋₁₀ aryl groupsthat may be mentioned include phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyland the like, such as phenyl). For the avoidance of doubt, the point ofattachment of substituents on aryl groups may be via any carbon atom ofthe ring system.

As may be used herein, the term heteroaryl (or heteroaromatic) includesreferences to 5- to 14-(e.g. 5- to 10-) membered heteroaromatic groupscontaining one or more heteroatoms selected from oxygen, nitrogen and/orsulfur. Such heteroaryl groups may comprise one, two, or three rings, ofwhich at least one is aromatic. Substituents onheteroaryl/heteroaromatic groups may, where appropriate, be located onany atom in the ring system including a heteroatom. The point ofattachment of heteroaryl/heteroaromatic groups may be via any atom inthe ring system including (where appropriate) a heteroatom. Bicyclicheteroaryl/heteroaromatic groups may comprise a benzene ring fused toone or more further aromatic or non-aromatic heterocyclic rings, inwhich instances, the point of attachment of the polycyclicheteroaryl/heteroaromatic group may be via any ring including thebenzene ring or the heteroaryl/heteroaromatic or heterocyclyl ring.Examples of heteroaryl/heteroaromatic groups that may be mentionedinclude pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl,imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl,azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl,quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl,benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl andpurinyl. The oxides of heteroaryl/heteroaromatic groups are alsoembraced within the scope of the invention (e.g. the N-oxide). As statedabove, heteroaryl includes polycyclic (e.g. bicyclic) groups in whichone ring is aromatic (and the other may or may not be aromatic). Hence,other heteroaryl groups that may be mentioned include e.g.benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole,3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl,thiochromanyl and the like.

For the avoidance of doubt, as used herein, references to heteroatomswill take their normal meaning as understood by one skilled in the art.Particular heteroatoms that may be mentioned include phosphorus,selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g.oxygen, nitrogen and sulfur).

For the avoidance of doubt, references to polycyclic (e.g. bicyclic)groups (e.g. when employed in the context of heterocyclyl groups) willrefer to ring systems wherein more than two scissions would be requiredto convert such rings into a straight chain, with the minimum number ofsuch scissions corresponding to the number of rings defined (e.g. theterm bicyclic may indicate that a minimum of two scissions would berequired to convert the rings into a straight chain). For the avoidanceof doubt, the term bicyclic (e.g. when employed in the context ofheterocyclyl groups) may refer to groups in which the second ring of atwo-ring system is formed between two adjacent atoms of the first ring,and may also refer to groups in which two non-adjacent atoms are linkedby either an alkylene or heteroalkylene chain (as appropriate), whichlater groups may be referred to as bridged.

For the avoidance of doubt, when an aryl or an heteroaryl group issubstituted with a group via a double bond, such as ═O, it is understoodthat the aryl or heteroaryl group is partly aromatic, i.e. the aryl orheteroaryl group consists of at least two rings where at least one ringis not aromatic.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent. For example, in the situation in which two or more Ygroups are present, those Y groups may be the same or different.Similarly, where two or more Y groups are present and each representR^(a3), the R^(a3) groups in question may be the same or different.Likewise, when more than one R^(a1) is present and each independentlyrepresents C₁₋₆ alkyl substituted by one or more G^(1a) group, theidentities of each G^(1a) are in no way interdependent.

For the avoidance of doubt, when a term such as “A^(a1) to A^(f1)” isemployed herein, this will be understood by the skilled person to meanA^(a1), A^(b1), A^(c1), A^(d1), A^(e1) and f^(f1) inclusively. Unlessotherwise stated, the same reasoning will apply to other such terms usedherein.

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation, e.g. from a reaction mixture, to a usefuldegree of purity.

All embodiments of the invention and particular features mentionedherein may be taken in isolation or in combination with any otherembodiments and/or particular features mentioned herein (hencedescribing more particular embodiments and particular features asdisclosed herein) without departing from the disclosure of theinvention.

Particular compounds of the invention that may be mentioned includethose in which n represents 2.

Further compounds of the invention that may be mentioned include thosein which n represents 1.

Particular compounds of the invention that may be mentioned includethose in which X represents C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl(e.g. C₂₋₈ alkyl).

More particularly, compounds of the invention that may be mentionedinclude those in which:

when X represents C₁ alkyl (such as in embodiments where X representsC₁₋₈ alkyl), X is substituted with at least one (e.g. one) Y group;and/or (e.g. and) when X represents other than C₁ alkyl (e.g. where Xrepresents Cm alkyl, such as in embodiments where X represents C₁₋₈alkyl), X is optionally substituted with at least one (e.g. one) Y group(e.g. X is unsubstituted).

Thus, in particular embodiments of compounds of the invention, X doesnot represent unsubstituted C₁ alkyl (although, for the avoidance ofdoubt, such a feature of any embodiments described herein is not hereinreferred to as a “proviso”).

Further compounds of the invention that may be mentioned include thosein which X represents unsubstituted C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or C₂₋₁₂alkynyl (e.g. C₂₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, such as C₂₋₈alkyl).

Yet further compounds of the invention that may be mentioned includethose in which X represents unsubstituted C₃₋₈ alkyl, C₃₋₈ alkenyl orC₃₋₈ alkynyl (e.g. C₃₋₈ alkyl, such as cyclic or part cyclic C₃₋₆alkyl).

Yet further compounds of the invention that may be mentioned includethose in which X represents unsubstituted C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl orC₂₋₁₂ alkynyl (e.g. C₂₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, such asC₂₋₈ alkyl).

Particular compounds of the invention that may be mentioned includethose in which each Y independently represents halo, Rai, —CN,—C(O)N(R^(c3))R^(d3), —N(R^(p3))C(O)R^(b3) (e.g. —N(H)C(O)R^(b3)),—C(O)ORe³, —N(R^(j3))R^(k3), —OR^(l3), —SR^(m3) or ═O.

More particular compounds of the invention that may be mentioned includethose in which each Y independently represents halo (e.g. fluoro) or,particularly, R^(a3), —C(O)N(Re³)R^(d3), —N(H)C(O)R^(b3), —C(O)ORe³,—N(RP)R^(k3) or —OR^(l3).

Particular compounds of the invention (i.e. compounds of formula I,including compounds of the first aspect of the invention) that may bementioned include those in which:

-   X represents C₂₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₂₋₆    alkyl, such as C₂₋₃ alkyl) substituted by one or more groups    independently selected from Y;-   each Y independently represents halo, —CN, -A^(a2)-C(O)R^(b3),    -A^(b2)-C(O)N(R^(c3))R^(d3), -A^(c2)-C(O)OR^(e3),    -A^(d2)-S(O)_(q)R^(f3), -A^(e2)-S(O)_(g)N(R^(g3))R^(h3),    —N(R^(j3))R^(k2), —OR^(l3), —SR^(m3) or ═O;-   each Q^(a2) to Q^(c2) independently represents ═O, ═S, ═NR^(n3) or    ═N(OR^(o3));-   each A^(a2) to A^(e2) independently represents a single bond,    —N(R^(p3))— or —O—;-   each R^(f2) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more groups independently selected from G^(2a), heterocyclyl    optionally substituted by one or more groups independently selected    from G^(2b), aryl optionally substituted by one or more groups    independently selected from G^(2c), or heteroaryl optionally    substituted by one or more groups independently selected from    G^(2d);-   each R^(b3), R^(c3), R^(d3), R^(e3), R^(g3), R^(h3), R^(k3), R^(l3),    R^(m3), R^(n3), R^(o3) and R^(p3) independently represents H, C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more groups independently selected    from G^(2a), heterocyclyl optionally substituted by one or more    groups independently selected from G^(2b), aryl optionally    substituted by one or more groups independently selected from    G^(2c), or heteroaryl optionally substituted by one or more groups    independently selected from G^(2d), or any two R^(c3) and R^(d3),    R^(g3) and R^(h3) and/or R^(j3) and R^(k3) are linked together to    form, along with the nitrogen atom to which they are attached, a 3-    to 6-membered ring, which ring optionally contains one further    heteroatom and which ring optionally is substituted by one or more    groups independently selected from heterocyclyl optionally    substituted by one or more groups independently selected from    G^(2b), aryl optionally substituted by one or more groups    independently selected from G^(2c), or heteroaryl optionally    substituted by one or more groups independently selected from    G^(2d), and ═O;-   each G^(2a) independently represents halo, —CN, —N(R^(j4))R^(k4),    —OR^(l4), —SR^(m4) or ═O;-   each G^(2b) independently represents halo, R^(a4), —CN,    —N(R^(j4))R^(k4), —OR^(l4), —SR^(m4) or ═O;-   each G^(2c) and G^(2d) independently represents halo, R^(a4), —CN,    -A^(a3)-C(Q^(a3))R_(b4), -A^(b3)-C(Q^(b3))N(R_(c4))R_(d4),    -A^(c3)-C(Q^(c4))OR^(e4), -A^(d3)-S(O)^(q)R^(f4),    -A^(e3)-S(O)_(q)N(R^(g4))R^(h4), -A^(f3)-S(O)_(q)OR^(l4), —N₃,    —N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂, —OR^(l4) or —SR^(m4);-   each Q^(a3) to Q^(c3) independently represents ═O, ═S, ═NR^(n4) or    ═N(OR^(o4));-   each A^(a3) to A^(f3) independently represents a single bond,    —N(R^(p4))— or —O—;-   each R^(a3) and R^(f3) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more groups independently selected from    G^(3a), or heterocyclyl optionally substituted by one or more groups    independently selected from G^(3b);-   each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(i4), R^(j4),    R^(k4), R^(l4), R^(m4), R^(n4), R^(o4) and R^(p4) independently    represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl) each optionally substituted by one or more groups    independently selected from G^(3a) or heterocyclyl optionally    substituted by one or more groups independently selected from    G^(3b), or-   any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(i4) and R^(k4)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected G^(3b);-   each G^(3a) and G^(3b) independently represents halo, R^(a5), —CN,    —N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O;-   each R^(a5) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more groups independently selected from G⁴;-   each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H,    C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more groups independently selected    from G⁴, or-   each R^(b5) and R^(c5) are linked together to form, together with    the nitrogen atom to which they are attached, a 3- to 6-membered    ring, which ring optionally contains one further heteroatom and    which ring optionally is substituted by one or more groups    independently selected G⁴;-   each G⁴ independently represents halo, R^(a6), —CN,    —N(R^(b6))R^(c6), —OR^(d6) or ═O;-   each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) optionally substituted by one or more    fluoro;-   each R^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more fluoro; and/or (e.g. and)-   each p and q independently represents 1 or 2.

More particular compounds of the invention that may be mentioned includethose in which: X represents C₂₋₈alkyl (e.g. C₂₋₅ alkyl) substituted byone or more groups independently selected from Y;

-   each Y independently represents fluoro, —N(H)—C(O)R^(b3),    —C(O)OR^(e3), —N(H)—S(O)₂R^(f3), —S(O)₂R^(f3),    —N(H)—S(O)_(q)N(R^(g3))R^(h3), —N(R^(j3))R^(k3) or —ORB;

each R^(b3), R^(e3), R^(f3), R^(g3), R^(h3), R^(e3), R^(j3), R^(k3) andR^(l3) independently represents H or C₁₋₃alkyl, or any two R^(g3) andR^(h3) and/or R^(j3) and R^(k3) are linked together to form, togetherwith the nitrogen atom to which they are attached, a 3- to 6-memberedring, which ring optionally contains one further nitrogen and which ringoptionally is substituted by one or more C₁₋₃ alkyl.

Yet more particular compounds of the invention that may be mentionedinclude those in which:

-   X represents C₂₋₅ alkyl, C₂₋₅ alkenyl or C₂₋₅ alkynyl (e.g. C₂₋₅    alkyl) substituted by one or more groups independently selected from    Y;-   each Y independently represents fluoro, —N(R^(j3))R^(k3) or    —OR^(l3); and/or-   each R^(j3), R^(k3) and R^(l3) independently represents H or C₁₋₃    alkyl (e.g. —CH₃), or R^(j3) and R^(k3) are linked together to form,    together with the nitrogen atom to which they are attached, a 3- to    6-membered ring (e.g a 5- to 6-membered ring), which ring optionally    contains one further nitrogen and which ring optionally is    substituted by one or more (e.g. one) C₁₋₃ alkyl (e.g. —CH₃).

Particular compounds of the invention that may be mentioned includethose in which:

-   X represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl, such as C₁₋₄ alkyl) each optionally substituted by Y (e.g. X    is unsubstituted or, in certain embodiments, substituted by at least    one Y, such as wherein X is substituted by one Y);-   Y represents Rai;-   R^(a3) represents heterocyclyl optionally substituted by one or more    groups independently selected from G^(2b);-   each G^(2b) independently represents halo, R^(a4), —CN, —C(O)R^(b4),    —N(R^(j4))R^(k4), —OR^(l4), —SR^(m4) or ═O;-   each R^(a4) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more groups independently selected from G^(3a), or heterocyclyl    optionally substituted by one or more groups independently selected    from G^(3b);-   each R^(b4), R^(j4), R^(k4), R^(l4) and R^(m4) independently    represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl) optionally substituted by one or more groups independently    selected from G^(3a), or heterocyclyl optionally substituted by one    or more groups independently selected from G^(3b), or-   R^(j4) and R^(k4) are linked together to form, together with the    nitrogen atom to which they are attached, a 3- to 6-membered ring,    which ring optionally contains one further heteroatom and which ring    optionally is substituted by one or more groups independently    selected G^(3b);-   each G^(3a) and G^(3b) independently represents halo, R^(a5), —CN,    —N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O; each R^(a5)    independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl    (e.g. C₁₋₆ alkyl) each optionally substituted by one or more groups    independently selected from G⁴;-   each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H,    or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more groups independently selected    from G, or-   each R^(b5) and Roy are linked together to form, together with the    nitrogen atom to which they are attached, a 3- to 6-membered ring,    which ring optionally contains one further heteroatom and which ring    optionally is substituted by one or more groups independently    selected G⁴;-   each G⁴ independently represents halo, R^(a6), —CN,    —N(R^(b6))R^(c6), —OR^(d6) or ═O;-   each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more fluoro;-   each R^(b6), R^(cb) and R^(d6) independently represents H or C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more fluoro; and/or (e.g. and)-   each p and q independently represents 1 or 2.

More particular compounds of the invention that may be mentioned includethose in which:

-   X represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl, such as C₁₋₄ alkyl) each optionally substituted by Y (e.g. X    is unsubstituted or, in certain embodiments, substituted by at least    one Y, such as wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents heterocyclyl optionally substituted by one or more    groups independently selected from G^(2b);-   each G^(2b) independently represents fluoro, R^(a4), —C(O)R^(b4),    —N(R^(j4))R^(k4), —OR^(l4) or ═O;-   each R^(a4) independently represents C₁₋₄ alkyl, C₂₋₄ alkenyl or    C₂₋₄ alkynyl (e.g. C₁₋₄ alkyl) each optionally substituted by one or    more groups independently selected from G^(3a);-   each R^(b4), R^(j4), R^(k4) and R^(j4) independently represents H,    or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more groups independently selected    from G^(3a);

each G^(3a) independently represents fluoro, R^(a5), —OR^(d5) or ═O;

each R^(a5) independently represents C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄alkynyl (e.g. C₁₋₄ alkyl) optionally substituted by one or more fluoro;and/or (e.g. and)

-   each R^(d5) independently represents H, or C₁₋₆ alkyl, C₂₋₆ alkenyl    or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one    or more fluoro.

Yet more particular compounds of the invention that may be mentionedinclude those in which:

-   X represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₄    alkyl) each optionally substituted by Y (e.g. X is unsubstituted or,    in certain embodiments, substituted by at least one Y, such as    wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents heterocyclyl optionally substituted by one or more    (e.g. one) G^(2b);-   each G^(2b) independently represents R^(a4) or —C(O)R^(b4); and/or    (e.g. and)-   each R^(a4) and R^(b4) independently represents C₁₋₄ alkyl (e.g.    —CH₃).

Even more particular compounds of the invention that may be mentionedinclude those in which:

-   X represents C₁₋₂ alkyl optionally substituted by Y (e.g. X is    unsubstituted or, in certain embodiments, substituted by at least    one Y, such as wherein X is substituted by one Y);-   Y represents R^(a3); and/or (e.g. and)-   R^(a3) represents piperidinyl (e.g. 1-piperidinyl), such as    unsubstituted piperidinyl.

Particular compounds of the invention that may be mentioned includethose in which:

-   X represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₄    alkyl) each optionally substituted by Y (e.g. X is unsubstituted or,    in certain embodiments, substituted by at least one Y, such as    wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents aryl optionally substituted by one or more groups    independently selected from G^(2c);-   each G^(2c) independently represents halo, R^(a4), —CN,    -A^(a3)-C(Q^(a3))R^(b4), -A^(b3)-C(Q^(b3))N(R^(c4))R^(d4),    -A^(c3)-C(Q^(c3))OR^(e4), -A^(d3)-S(O)_(q)R^(f4),    -A^(e3)-S(O)_(q)N(R^(g4))R^(h4), -A^(f3)-S(O)_(q)R^(i4), —N₃,    —N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂, —OR′ or —SR^(m4);-   each Q^(a3) to Q^(c3) independently represents ═O, ═S, ═NR^(n4) or    ═N(OR^(o4));-   each A^(a3) to A^(f3) independently represents a single bond,    —N(R^(p4))— or —O—;-   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. O₁₋₆ alkyl) each optionally    substituted by one or more groups independently selected from    G^(3b), or heterocyclyl optionally substituted by one or more groups    independently selected from G^(3b);-   each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(i4), R^(j4),    R^(k4), R^(l4), R^(m4), R^(n4), R^(o4) and R^(p4) independently    represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl) each optionally substituted by one or more groups    independently selected from G^(3a) or heterocyclyl optionally    substituted by one or more groups independently selected from    G^(3b), or-   any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(i4) and R^(k4)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    G^(3b);

each G^(3a) and G^(3b) independently represents halo, R^(a5), —CN,—N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O; each R^(a5) independentlyrepresents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl)each optionally substituted by one or more groups independently selectedfrom G⁴;

-   each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H,    C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more groups independently selected    from G⁴, or-   each R^(b5) and R^(c5) are linked together to form, together with    the nitrogen atom to which they are attached, a 3- to 6-membered    ring, which ring optionally contains one further heteroatom and    which ring optionally is substituted by one or more groups    independently selected from G⁴;-   each G⁴ independently represents halo, R^(a6), —CN,    —N(R^(b6))R^(c6), —OR^(d6) or ═O;-   each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more fluoro;-   each R^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more fluoro; and/or (e.g. and) each    p and q independently represents 1 or 2.

More particular compounds the invention that may be mentioned includethose in which:

-   X represents C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl (e.g. C₁₋₄    alkyl) each optionally substituted by Y (e.g. X is unsubstituted or,    in certain embodiments, substituted by at least one Y, such as    wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents aryl optionally substituted by one or more (e.g.    one or two) groups independently selected from G^(2c);

each G^(2c) independently represents halo, R^(a4), —CN,-A^(a3)-C(O)R^(b4), -A^(b3)-C(O)N(R^(c4))R^(d4), -A^(c3)-C(O)OR^(e4),-A^(d3)-S(O)_(Q)R^(f4), -A^(e3)-S(O)_(q)N(R^(g4))R^(ha),—N(R^(j4))R^(k4) or —OR^(l4);

-   each A^(a3) to A^(c3) independently represents a single bond or    —N(R^(p4))—;-   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more fluoro;

each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(j4), R^(k4),R^(l4) and R^(p4) independently represents H, or C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted byone or more fluoro, or

-   any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(j4) and R^(k4)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    G^(3b);-   each G^(3b) independently represents fluoro, R^(a5) or ═O;-   each R^(a4) independently represents C₁₋₃ alkyl optionally    substituted by one or more fluoro; and/or (e.g. and)-   each p and q independently represents 1 or 2.

Yet more particular compounds of the invention that may be mentionedinclude those in which:

-   X represents C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl (e.g. C₁₋₄    alkyl) each optionally substituted by Y (e.g. X is unsubstituted or,    in certain embodiments, substituted by at least one Y, such as    wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents aryl optionally substituted by G^(2c);-   G^(2c) represents halo, R^(a4), —CN, —C(O)N(R^(c4))R^(d4),    —C(O)OR^(e4), —S(O)₂R^(f4), —S(O)₂N(R^(g4))R^(h4), —N(R^(j4))R^(k4)    or —OR^(l4);-   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more fluoro; and/or (e.g. and)-   each R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(j4), R^(k4), R^(l4)    and R^(l4) independently represents H, or C₁₋₆ alkyl, C₂₋₆ alkenyl    or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one    or more fluoro.

Even more particular compounds of the invention that may be mentionedinclude those in which each G^(2c) represents fluoro, chloro, —CH₃,—CF₃, —CN, —C(O)NH₂, —C(O)OCH₃, —N(CH₃)₂ or —OCH₃.

Particular compounds of the invention that may be mentioned includethose in which:

-   X represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl, such as C₁₋₄ alkyl) each optionally substituted by Y (e.g. X    is unsubstituted or, in certain embodiments, substituted by at least    one Y, such as wherein X is substituted by one Y);-   Y represents R^(a2);-   R^(a2) represents heteroaryl optionally substituted by one or more    groups independently selected from G^(2d);-   each G^(2d) independently represents halo, R^(a4), —CN,    -A^(a3)-C(Q^(a3))R^(b4), -A^(b3)-C(Q^(b3))N(R^(c4))R^(d4),    -A^(c3)-C(Q^(c3))OR^(e4), -A^(d3)-S(O)_(q)R^(f4),    -A^(e3)-S(O)_(q)N(R^(g4))R^(b4), -A^(f3)-S(O)_(q)OR^(i4), —N₃,    —N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂, —OR′ or —SR^(m4);-   each Q^(a3) to Q^(c3) independently represents ═O, ═S, ═NR^(n4) or    ═N(OR^(o4));-   each A^(a3) to A^(f3) independently represents a single bond,    —N(R^(p4))— or —O—;-   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more groups independently selected from G³a,    or heterocyclyl optionally substituted by one or more groups    independently selected from G^(3b);-   each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(i4), R^(j4),    R^(k4), R^(l4), R^(m4), R^(n4), R^(o4) and R^(p4) independently    represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆    alkyl) each optionally substituted by one or more groups    independently selected from G^(3a), or heterocyclyl optionally    substituted by one or more groups independently selected from G³, or-   any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(j4) and R^(k4)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    G^(3b);-   each G^(3a) and G^(3b) independently represents halo, R^(a5), —CN,    —N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O; each R^(a5)    independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl    (e.g. C₁₋₆ alkyl) each optionally substituted by one or more groups    independently selected from G⁴;-   each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H,    or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more groups independently selected    from G⁴, or-   each R^(b5) and RG⁵ are linked together to form, together with the    nitrogen atom to which they are attached, a 3- to 6-membered ring,    which ring optionally contains one further heteroatom and which ring    optionally is substituted by one or more groups independently    selected from G⁴;-   each G⁴ independently represents halo, R^(ab), —CN,    —N(R^(b6))R^(c6), —OR^(d6) or ═O;-   each R^(a5) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more fluoro;-   each R^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each    optionally substituted by one or more fluoro; and/or (e.g. and) each    p and q independently represents 1 or 2.

More particular compounds of the invention that may be mentioned includethose in which:

-   X represents C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl (e.g. C₁₋₄    alkyl) each optionally substituted by Y (e.g. X is unsubstituted or,    in certain embodiments, substituted by at least one Y, such as    wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents heteroaryl optionally substituted by one or more    (e.g. one or two) groups independently selected from G^(2d);-   each G^(2d) independently represents halo, R^(a3), —CN,    -A^(a3)-C(O)R^(b4), -A^(b3)-C(O)N(R^(c4))R^(d4),    -A^(c3)-C(O)OR^(e4), -A^(d3)-S(O)_(q)R^(f4),    -A^(e3)-S(O)_(q)N(R^(g4))R^(h4), —N(R^(j4))R^(k4) or —OR^(l4);-   each A^(a3) to A^(c3) independently represents a single bond or    —N(R^(p4))—;-   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more fluoro;-   each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(j4), R^(k4),    R^(l4) and R^(p4) independently represents H, or C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more fluoro, or-   any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(j4) and R^(k4)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    G^(3b);-   each G^(3b) independently represents fluoro, R^(a5) or ═O;-   each R^(a5) independently represents C₁₋₃ alkyl optionally    substituted by one or more fluoro; and/or (and)-   each p and q independently represents 1 or 2.

Yet more particular compounds of the invention that may be mentionedinclude those in which:

-   X represents C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl (e.g. C₁₋₄    alkyl) each optionally substituted by Y (e.g. X is unsubstituted or,    in certain embodiments, substituted by at least one Y, such as    wherein X is substituted by one Y);-   Y represents R^(a3);-   R^(a3) represents heteroaryl optionally substituted by G^(2d);-   G^(2d) represents halo, R^(a4), —CN, —C(O)N(R^(c4))R^(d4),    —C(O)OR^(e4), —S(O)₂R^(f4), —S(O)₂N(R^(g4))R^(h4), —N(R^(j4))R^(k4)    or —OR^(l4);-   each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally    substituted by one or more fluoro; and/or (e.g. and)-   each R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(j4), R^(k4), R^(l4)    and R^(l4) independently represents H, or C₁₋₆ alkyl, C₂₋₆ alkenyl    or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one    or more fluoro.

Even more particular compounds of the invention that may be mentionedinclude those in which:

-   R^(a3) represents heteroaryl (e.g. furanyl (e.g. 2-furanyl) or    pyrazinyl) optionally substituted (e.g. unsubstituted) by G^(2d);    and/or (e.g. and)-   G^(2d) represents fluoro, chloro or C₁₋₃ alkyl (e.g. —CH₃).

Particular compounds of the invention that may be mentioned includethose in which R¹, R² and R³ each independently represent H, halo (e.g.chloro or fluoro, such as chloro), R^(a1), —N(R^(j1))R^(k1), —OR^(l1) or—SR^(m1) (such as H, halo (e.g. chloro or fluoro, such as chloro),R^(a1)—N(R^(j1))R^(k1) or —OR^(l1)).

More particular compounds of the invention that may be mentioned includethose in which:

-   each R^(ai) and R^(n) independently represents C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl each optionally substituted by one or more    groups independently selected from G^(1a), or heterocyclyl    optionally substituted by one or more groups independently selected    from G^(1b); and-   each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1), R^(j1),    R^(k1), R^(l1), R^(m1), R_(n1), R^(o1) and R^(p1) independently    represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each    optionally substituted by one or more groups independently selected    from G^(1a) or heterocyclyl optionally substituted by one or more    groups independently selected from G^(1b); or-   any of R^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1)    are linked together to form, together with the nitrogen atom to    which they are attached, a 3- to 6-membered ring, which ring    optionally contains one further heteroatom and which ring optionally    is substituted by one or more groups independently selected from    halo, and C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl each optionally    substituted by one or more halo, and ═O.

Yet more particular compounds of the invention that may be mentionedinclude those in which:

-   R¹ represents halo (e.g. chloro), —N(R^(j1))R^(k1), —OR^(l1) or    —SR^(m1) (e.g. halo, —N(R^(j1))R^(k1) or —OR^(l1));-   each R² and R³ each independently represent H, halo, R^(a1),    —N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1) (e.g. H, halo, R^(a1),    —N(R^(j1))R^(k1) or —OR^(l1)); and/or (e.g. and)-   each R^(a1), R^(j1), R^(k1), R^(l1) and R^(m1) independently    represent C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl,    such as —CH₃) each optionally substituted by one or more fluoro.

In particular embodiments that may be mentioned, only R^(c1) and R^(d1),and/or R^(g1) and R^(h1) may alternatively be linked together in themanner described herein.

For example, compounds of formula I (i.e. compounds of the invention)that may be mentioned include those in which:

-   R¹ represents —N(R^(j1))R^(k1) or —OR^(l1);-   each R² and R³ each independently represent H or —N(R^(j1))R^(k1),    —OR^(l1), or heterocyclyl optionally substituted by one G^(1b);-   each R^(j1) and R^(k1) independently represents H or C₁₋₆ alkyl,    C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl),-   or R^(j1) and R^(k1) are linked together to form, along with the    nitrogen atom to which they are attached, a 3- to 6-membered ring,    which ring optionally contains one further heteroatom and which ring    optionally is substituted by one or more groups independently    selected from C₁₋₃ alkyl;-   each R^(l1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted by one or    more fluoro (e.g. so forming a —CH₃, —CHF₂ or —CF₃ group); and/or    (and)-   G^(1b) represents C₁₋₃ alkyl and ═O.

Further compounds of the invention that may be mentioned include thosein which R² and R³ each independently represent H, halo (e.g. fluoro orchloro, such as chloro), —N(R^(j1))R^(k1) or —OR^(l1).

In particular, compounds of the invention that may be mentioned includethose in which:

-   R¹ represents halo (e.g. chloro), —N(R^(j1))R^(k1) or —OR^(l1);-   each R² and R³ each independently represent H, halo (e.g. chloro),    —N(R^(j1))R^(k1) or —OR^(l1);-   each R^(l1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or    C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) optionally substituted by one or more    fluoro (such as —CH₃, —CHF₂ or —CF₃ group) group); and/or (e.g. and)-   each R^(j1) and R^(k1) independently represent C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) optionally substituted by    one or more fluoro (such as a —CH₃ group).

For example, particular compounds the invention that may be mentionedinclude those in which:

-   R¹ represents —OR^(l1);-   each R² and R³ each independently represent H or —OR^(l1); and/or    (and)-   each R^(l1) independently represents C₁₋₆ alkyl (e.g. —CH₃)    optionally substituted by one or more fluoro (e.g. so forming —CF₃).

Particular compounds of the invention that may be mentioned includethose in which each of R² and R³ represent H.

For example, in particular embodiments, there is provided compounds ofthe invention wherein:

-   R² and R³ represent H; and/or (e.g. and)-   R¹ represents —OC₁₋₆ alkyl optionally substituted by one or more    fluoro (e.g. —OCH₃).

In a further embodiment, there is provided compounds of the inventionwherein:

-   R² and R³ represent H; and/or (e.g. and)-   R¹ represents halo (e.g. chloro), —N(CH₃)₂, or —OCH₃.

In a yet further embodiment, there is provided compounds of theinvention wherein:

-   R² and R³ represent H; and/or (e.g. and)-   R¹ represents —OCH₃.

As indicated herein above, particular features and embodiments asdescribed herein may be combined without departing from the teaching ofthe invention.

For example, in a particular embodiment of the invention (e.g. aparticular embodiment of the first aspect of the invention), there isprovided compounds of the invention wherein:

-   X represents unsubstituted C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl or C₁₋₁₂    alkynyl (e.g. a C₂₋₈ alkyl, including cyclic or part cyclic C₃₋₆    alkyl);-   R¹ represents halo, —N(R^(j1))R^(k1) or —OR^(l1); and-   each R² and R³ independently represents H, halo, R^(a1),    —N(R^(j1))R^(k1) or

In a particular embodiments of the invention that may be mentioned,there is provided compounds of the invention wherein:

-   X represents an unsubstituted C₂₋₈ alkyl group;-   X represents an unsubstituted cyclic or part cyclic C₃₋₆ alkyl    group;-   X represents C₁₋₄ alkyl substituted with a heterocyclyl group as    defined in formula I (including all features and embodiments    thereof);-   X represents C₁₋₄ alkyl substituted with an aryl group as defined in    formula I (including all features and embodiments thereof);-   X represents C₁₋₄ alkyl substituted with a monocyclic heteroaryl    group as defined in formula I (including all features and    embodiments thereof);-   X represents C₁₋₄ alkyl substituted with a five membered heteroaryl    group as defined in formula I (including all features and    embodiments thereof);-   X represents C₁₋₄ alkyl substituted with a six membered heteroaryl    group as defined in formula I (including all features and    embodiments thereof); or-   X represents C₁₋₄ alkyl substituted with a bicyclic heteroaryl group    as defined in formula I (including all features and embodiments    thereof).

For the avoidance of doubt, in a particular embodiments of theinvention, there is provided compounds of the invention wherein R² andR³ represent H and R¹ represents:

-   —OR^(l1) (e.g. —OCH₃);-   N(R^(j1))R^(k1) (e.g. —N(CH₃)₂); or chloro.

For the avoidance of doubt, the skilled person will understand that eachG^(3c) and G^(3d) may be construed relative to G^(3a) and G^(3b) in thesame manner as the corresponding G^(2c) and G^(2d) groups are construedrelative to construed relative to G^(1a) and G^(2b), i.e. such that:

-   G^(3c) and G^(3d) independently representing halo, R^(a5), —CN,    -A^(a4)-C(Q^(a4))R^(b5), -A^(b4)-C(Q^(b4))N(R^(c5))R^(d5),    -A^(c4)-C(Q^(c4))OR^(e5), -A^(d5)-S(O)_(q)R^(f5),    -A^(e4)-S(O)_(g)N(R^(g5))R^(h5), -A^(f4)-S(O)_(q)OR^(i5), —N₃,    —N(R^(j5))R^(k5), —N(H)CN, —NO₂, —ONO₂, —OR^(l5) or —SR^(m5),-   each Q^(a4) to Q^(c4) independently represents ═O, ═S, ═NR^(a5) or    ═N(OR^(o5));-   each A^(a4) to A^(f4) independently represents a single bond,    —N(R^(p5))— or —O—;-   with each R^(f5) to R^(p5) independently representing H, or C₁₋₆    alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by    one or more groups independently selected from G⁴, or with each    R^(g5) and R^(h5), and R^(j5) and R^(k5) being linked together to    form, together with the nitrogen atom to which they are attached, a    3- to 6-membered ring, which ring optionally contains one further    heteroatom and which ring optionally is substituted by one or more    groups independently selected from G⁴.

Particular compounds of the invention (including compounds of formula Iand all embodiments and particular forms thereof) that may be mentionedinclude the compounds of the examples as provided herein, or apharmaceutically acceptable salt thereof.

Where an example compound is indicated to have been obtained in aparticular salt form, the skilled person will understand that particularcompounds of the invention that may be mentioned include the free baseor free acid (as appropriate) of that compound, and vice versa. Further,where an example compound is indicated to have been obtained in aparticular salt form, particular compounds of the invention that may bementioned include other (i.e. different) pharmaceutically acceptablesalts of that compound.

Thus, for the avoidance of doubt, particular compounds of the inventionthat may be mentioned include:

-   2-benzylsulfonyl-6-methoxy-3-nitropyridine;-   2-cyclopentylsulfonyl-6-methoxy-3-nitropyridine;-   2-hexylsulfonyl-6-methoxy-3-nitropyridine;-   2-benzylsulfonyl-6-chloro-3-nitropyridine;-   6-chloro-2-(cyclopentylsulfonyl)-3-nitropyridine;-   6-chloro-2-(hexylsulfonyl)-3-nitropyridine;-   2-benzylsulfonyl-6-dimethylamino-3-nitropyridine;-   2-cyclopentylsulfonyl-6-dimethylamino-3-nitropyridine;-   6-dimethylamino-2-hexylsulfonyl-3-nitropyridine;-   2-(ethylsulfonyl)-6-methoxy-3-nitropyridine;-   2-(isopropylsulfonyl)-6-methoxy-3-nitropyridine;-   6-methoxy-3-nitro-2-(octylsulfonyl)pyridine;-   2-(cyclopropylsulfonyl)-6-methoxy-3-nitropyridine;-   6-methoxy-3-nitro-2-((5,5,5-trifluoropentyl)sulfonyl)pyridine;-   N-(2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethyl)acetamide;-   methyl 3-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)propanoate;-   3-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)propan-1-ol;-   6-methoxy-3-nitro-2-((2-(piperidin-1-yl)ethyl)sulfonyl)pyridine;-   2-((2-chlorobenzyl)sulfonyl)-6-methoxy-3-nitropyridine;-   2-((3-chlorobenzyl)sulfonyl)-6-methoxy-3-nitropyridine;-   2-((4-chlorobenzyl)sulfonyl)-6-methoxy-3-nitropyridine;-   2-((4-fluorobenzyl)sulfonyl)-6-methoxy-3-nitropyridine;-   6-methoxy-2-((4-methylbenzyl)sulfonyl)-3-nitropyridine;-   6-methoxy-2-((4-methoxybenzyl)sulfonyl)-3-nitropyridine;-   6-methoxy-3-nitro-2-((4-(trifluoromethoxy)benzyl)sulfonyl)pyridine;-   6-methoxy-3-nitro-2-(phenethylsulfonyl)pyridine;-   6-methoxy-3-nitro-2-((3-phenylpropyl)sulfonyl)pyridine;-   6-methoxy-3-nitro-2-((2-phenoxyethyl)sulfonyl)pyridine;-   2-((furan-2-ylmethyl)sulfonyl)-6-methoxy-3-nitropyridine; and-   2-(2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethyl)pyrazine,-   and pharmaceutically acceptable salts thereof.

Compositions and Medical Uses

As discussed hereinbefore, compounds of the invention, and thereforecompositions and kits comprising the same, are useful aspharmaceuticals.

According to a second aspect of the invention there is provided acompound of the invention, as hereinbefore defined (i.e. in the firstaspect of the invention, including all embodiments and particularfeatures therein, but without the provisos), for use as apharmaceutical. Further, there is provided a compound of the invention,as hereinbefore defined, for use in medicine.

In a particular embodiment of the second aspect of the invention, thecompound of the invention is a compound of the invention but withproviso (B) (i.e. including proviso (B) as defined in the first aspectof the invention).

In a particular embodiment of the second aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the provisos).

As indicated herein, compounds of the invention may be of particular usein treating cancers.

Thus, in a third aspect of the invention, there is provided a compoundof the invention, as hereinbefore defined (i.e. in the first aspect ofthe invention, including all embodiments and particular featurestherein, but without the provisos), for use in the treatment of cancer.

In an alternative third aspect of the invention, there is provided theuse of a compound of the invention, as hereinbefore defined, in themanufacture of a medicament for the treatment of cancer.

In a further alternative third aspect of the invention, there isprovided a method of treating cancer comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the invention.

In a particular embodiment of the third aspect of the invention, thecompound of the invention is a compound of the invention but withproviso (B) (i.e. including proviso (B) as defined in the first aspectof the invention).

In a particular embodiment of the third aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the provisos).

The skilled person will understand that references to the treatment of aparticular condition (or, similarly, to treating that condition) taketheir normal meanings in the field of medicine.

In particular, the terms may refer to achieving a reduction in theseverity of one or more clinical symptom associated with the condition.For example, in the case of a cancer, the term may refer to achieving areduction of the amount of cancerous cells present (e.g. in the case ofa cancer forming a solid tumour, indicated by a reduction in tumourvolume).

As used herein, references to patients will refer to a living subjectbeing treated, including mammalian (e.g. human) patients.

As used herein, the term effective amount will refer to an amount of acompound that confers a therapeutic effect on the treated patient. Theeffect may be objective (i.e. measurable by some test or marker) orsubjective (i.e. the subject gives an indication of and/or feels aneffect).

Although compounds of the invention may possess pharmacological activityas such, certain pharmaceutically-acceptable (e.g. “protected”)derivatives of compounds of the invention may exist or be prepared whichmay not possess such activity, but may be administered parenterally ororally and thereafter be metabolised in the body to form compounds ofthe invention. Such compounds (which may possess some pharmacologicalactivity, provided that such activity is appreciably lower than that ofthe active compounds to which they are metabolised) may therefore bedescribed as “prodrugs” of compounds of the invention.

As used herein, references to prodrugs will include compounds that forma compound of the invention, in an experimentally-detectable amount,within a predetermined time, following enteral or parenteraladministration (e.g. oral or parenteral administration). All prodrugs ofthe compounds of the invention are included within the scope of theinvention.

Furthermore, certain compounds of the invention may possess no orminimal pharmacological activity as such, but may be administeredparenterally or orally, and thereafter be metabolised in the body toform compounds of the invention that possess pharmacological activity assuch. Such compounds (which also includes compounds that may possesssome pharmacological activity, but that activity is appreciably lowerthan that of the active compounds of the invention to which they aremetabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possesspharmacological activity, and/or are metabolised in the body followingoral or parenteral administration to form compounds that possesspharmacological activity.

Without wishing to be bound by theory, it is believed that compounds ofthe invention wherein n represents 1 may be metabolised in vivo to formcorresponding compounds of the invention wherein n represents 2.

As indicated herein, the compounds of the invention may be useful in thetreatment of cancer (i.e. particular cancers).

Particular cancers that may be mentioned include those selected from thegroup comprising:

-   soft tissue cancers, such as sarcoma (e.g. angiosarcoma,    fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,    fibroma, lipoma and teratoma;-   lung cancers, such as bronchogenic carcinoma (e.g. squamous cell,    undifferentiated small cell, undifferentiated large cell,    adenocarcinoma), alveolar (or bronchiolar) carcinoma, bronchial    adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma,    including non-small cell lung cancer;-   gastrointestinal cancers: such as esophageal cancers (e.g. squamous    cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach    cancers (e.g. carcinoma, lymphoma, leiomyosarcoma), pancreatic    cancers (e.g. ductal adenocarcinoma, insulinoma, glucagonoma,    gastrinoma, carcinoid tumors, vipoma), small bowel cancers (e.g.    adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,    leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel    cancers (e.g. adenocarcinoma, tubular adenoma, villous adenoma,    hamartoma, leiomyoma);-   genitourinary tract cancers, such as cancer of the kidney (e.g.    adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia),    bladder and urethra (e.g. squamous cell carcinoma, transitional cell    carcinoma, adenocarcinoma), prostate (e.g. adenocarcinoma, sarcoma),    testis (e.g. seminoma, teratoma, embryonal carcinoma,    teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell    carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);-   liver cancers, such as hepatoma (e.g. hepatocellular carcinoma),    cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular    adenoma, hemangioma;-   bone cancers, such as osteogenic sarcoma (e.g. osteosarcoma),    fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma,    Ewing's sarcoma, malignant lymphoma (e.g. reticulum cell sarcoma),    multiple myeloma, malignant giant cell tumor chordoma,    osteochronfroma (e.g osteocartilaginous exostoses), benign    chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and    giant cell tumors;-   cancers of the head and/or nervous system, such as cancer of the    skull (e.g. osteoma, hemangioma, granuloma, xanthoma, osteitis    deformans), meninges (e.g. meningioma, meningiosarcoma,    gliomatosis), brain (e.g. astrocytoma, medulloblastoma, glioma,    ependymoma, germinoma (pinealoma), glioblastoma multiform,    oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),    spinal cord (e.g. neurofibroma, meningioma, glioma, sarcoma);-   gynecological cancers, such as cancers of the uterus (e.g.    endometrial carcinoma), cervix (cervical carcinoma, pre-tumor    cervical dysplasia), ovaries (e.g. ovarian carcinoma (serous    cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified    carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell    tumors, dysgerminoma, malignant teratoma), cancers of the vulva    (e.g. squamous cell carcinoma, intraepithelial carcinoma,    adenocarcinoma, fibrosarcoma, melanoma), vagina (e.g. clear cell    carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal    rhabdomyosarcoma)), fallopian tubes (e.g. carcinoma);-   haematologic cancers, such as cancers of the blood and bone marrow    (e.g. myeloid leukemia (acute and chronic), acute lymphoblastic    leukemia, chronic lymphocytic leukemia, myeloproliferative diseases,    multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,    non-Hodgkin's lymphoma (malignant lymphoma);-   skin cancers, such as malignant melanoma, basal cell carcinoma,    squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi,    lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and    Adrenal glands; and-   neuroblastomas.

As used herein, references to cancerous cells and the like will includereferences to a cell afflicted by any one of the above identifiedconditions.

More particular cancers that may be mentioned include thosecorresponding to the cell lines used in the examples provided herein.

For example, particular cancers that may be mentioned include breastcancer (such as mammary adenocarcinoma, e.g. metastatic mammaryadenocarcinoma) and/or glioblastoma (such as glioblastoma multiform).

More particular cancers that may be mentioned include:

-   head and neck cancer (such as throat cancer, e.g. pharyngeal    squamous cell carcinoma);-   colon cancer (such as colorectal carcinoma);-   skin cancer (such as epidermoid (skin) carcinoma);-   gastrointestinal cancers (such as pancreatic cancer, e.g. pancreatic    ductal carcinoma);-   breast cancer (such as mammary adenocarcinoma, e.g. metastatic    mammary adenocarcinoma);-   lung cancer (such as carcinoma); and-   haematologic cancers (such as leukemia, e.g. acute monocytic    leukemia).

In particular embodiments, the cancer is a solid tumor cancer.

In more particular embodiments, the cancer is selected from pancreaticcancer, ovarian cancer and colorectal cancer.

For example, in certain embodiments, the cancer is selected fromcolorectal cancer (including those processing Ras mutations), small celllung cancer, non-small cell lung cancer (NSCLC), and glioma.

In other embodiments, the cancer is selected from non-small cell lungcancer, ovarian cancer, metastatic breast cancer, pancreatic cancer,hepatobiliary cancer (including hepatocellular cancer, bile duct cancerand cholangiocarcinoma), and gastric cancer.

In further embodiments, the cancer is selected from colorectal cancer(including Ras mutations), small cell lung cancer, non-small cell lungcancer, ovarian cancer, hepatobiliary cancer (including hepatocellularcancer, bile duct cancer and cholangiocarcinoma), gastric cancer,testicular cancer, and head and neck squamous cell carcinoma.

In certain embodiments of the present invention, the cancer is selectedfrom leukemia (including acute myeloid leukemia, acute lymphoblasticleukemia, chronic myeloid leukemia, and chronic lymphoid leukemia),lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma), and prostate cancer

The skilled person will understand that treatment with compounds of theinvention may further comprise (i.e. be combined with) furthertreatment(s) for the same condition. In particular, treatment withcompounds of the invention may be combined with means for the treatmentof cancer, such as treatment with one or more other therapeutic agentthat is useful in the in the treatment of cancer and/or one or morephysical method used in the treatment of cancer (such as treatmentthrough surgery), as known to those skilled in the art.

In particular, treatment with compounds of the invention may beperformed in patients who are being or have been (i.e. as part or of atreatment for the same condition, such as within a month of treatmentwith compounds of the invention, such as within two weeks, e.g. within aweek or, particularly, on the same day) treated with a therapeutic agentor physical method that is capable of causing (e.g. can be demonstratedto cause) an increase in reactive oxygen species.

For the avoidance of doubt, the skilled person will understand thattherapeutic agents or physical methods capable of causing (e.g. can bedemonstrated to cause) an increase in reactive oxygen species may notnecessarily be effective treatments per se, but will become effectivewhen used in combination with compounds of the invention.

For the avoidance of doubt, the skilled person will understand thatcompounds of the invention may also be used in combination with one ormore other therapeutic agent that is useful in the in the treatment ofcancer and/or one or more physical method used in the treatment ofcancer (such as treatment through surgery) wherein such methods do notcause an increase in reactive oxygen species.

In particular, treatment with compounds of the invention may beperformed in patients who are being or have been treated withradiotherapy.

Thus, there is also provided:

-   a method of treating cancer in a patient in need thereof wherein the    patient is administered a therapeutically effective amount of a    compound of the invention in combination with treatment by    radiotherapy (i.e. concomitantly or sequentially); and-   a compound of the invention for use in treating cancer in a patient    who is also being treated with radiotherapy.

Compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, sublingually, intranasally, topically, by anyother parenteral route or via inhalation, in a pharmaceuticallyacceptable dosage form.

Compounds of the invention may be administered alone or may beadministered by way of known pharmaceutical compositions/formulations,including tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike.

According to a fourth aspect of the invention there is thus provided apharmaceutical composition/formulation comprising a compound of theinvention as hereinbefore defined (i.e. in the first aspect of theinvention, including all embodiments and particular features therein,but without the provisos), and optionally (e.g. in admixture with) oneor more pharmaceutically acceptable adjuvant, diluent and/or carrier.

In a particular embodiment of the fourth aspect of the invention, thecompound of the invention is a compound of the invention but withproviso (B) (i.e. including proviso (B) as defined in the first aspectof the invention).

In a particular embodiment of the fourth aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the provisos).

The skilled person will understand that references herein to compoundsof the invention being for particular uses (and, similarly, to uses andmethods of use relating to compounds of the invention) may also apply topharmaceutical compositions comprising compounds of the invention asdescribed herein.

Compounds of the invention may be administered in the form of tablets orcapsules, e.g. time-release capsules that are taken orally.Alternatively, the compounds of the invention may be in a liquid formand may be taken orally or by injection. The compounds of the inventionmay also be in the form of suppositories, or, creams, gels, and foamse.g. that can be applied to the skin. In addition, they may be in theform of an inhalant that is applied nasally or via the lungs.

The skilled person will understand that compounds of the invention mayact systemically and/or locally (i.e. at a particular site).

Compounds of the invention may be administered orally, intravenously,subcutaneously, buccally, rectally, dermally, nasally, tracheally,bronchially, by any other parenteral route or via inhalation, in apharmaceutically acceptable dosage form. Alternatively, particularlywhere compounds of the invention are intended to act locally, compoundsof the invention may be administered topically.

Thus, in a particular embodiment, the pharmaceutical formulation isprovided in a pharmaceutically acceptable dosage form, including tabletsor capsules, liquid forms to be taken orally or by injection,suppositories, creams, gels, foams, or inhalants (e.g. to be appliedintranasally). For the avoidance of doubt, in such embodiments,compounds of the invention may be present as a solid (e.g. a soliddispersion), liquid (e.g. in solution) or in other forms, such as in theform of micelles.

In more particular embodiments, the pharmaceutical formulation isprovided the form of a tablets or capsules, liquid forms to be takenorally or by injection (e.g. a form suitable for intravenous injection).In particular, injection may take place using conventional means, andmay include the use of microneedles.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient ispresent in at least 1% (or at least 10%, at least 30% or at least 50%)by weight. That is, the ratio of active ingredient to the othercomponents (i.e. the addition of adjuvant, diluent and carrier) of thepharmaceutical composition is at least 1:99 (or at least 10:90, at least30:70 or at least 50:50) by weight.

As described herein, compounds of the invention may also be combinedwith one or more other (i.e. different, e.g. agents other than compoundsof formula I) therapeutic agents that are useful in the treatment ofcancer. Such combination products that provide for the administration ofa compound of the invention in conjunction with one or more othertherapeutic agent may be presented either as separate formulations,wherein at least one of those formulations comprises a compound of theinvention, and at least one comprises the other therapeutic agent, ormay be presented (i.e. formulated) as a combined preparation (i.e.presented as a single formulation including a compound of the inventionand the one or more other therapeutic agent).

Thus, according to a fifth aspect of the invention, there is provided acombination product comprising:

-   (A) a compound of the invention, as hereinbefore defined (i.e. in    the first aspect of the invention, including all embodiments and    particular features therein, but without the provisos); and-   (B) one or more other therapeutic agent that is useful in the    treatment of cancer, wherein each of components (A) and (B) is    formulated in admixture, optionally with one or more a    pharmaceutically-acceptable adjuvant, diluent or carrier.

In a sixth aspect of the invention there is provided a kit-of-partscomprising:

-   (a) a pharmaceutical formulation as hereinbefore defined (i.e. in    the fourth aspect of the invention); and-   (b) one or more other therapeutic agent that is useful in the    treatment of cancer, optionally in admixture with one or more    pharmaceutically-acceptable adjuvant, diluent or carrier,-   which components (a) and (b) are each provided in a form that is    suitable for administration in conjunction (i.e. concomitantly or    sequentially) with the other.

In a particular embodiment of the fifth and sixth aspects of theinvention, the compound of the invention is a compound of the inventionbut with proviso (B) (i.e. including proviso (B) as defined in the firstaspect of the invention).

The skilled person will understand that compounds of the invention, andpharmaceutically-acceptable salts thereof, may be administered (forexample, as formulations as described hereinabove) at varying doses,with suitable doses being readily determined by one of skill in the art.Oral, pulmonary and topical dosages (and subcutaneous dosages, althoughthese dosages may be relatively lower) may range from between about 0.01μg/kg of body weight per day (μg/kg/day) to about 200 μg/kg/day,preferably about 0.01 to about 10 μg/kg/day, and more preferably about0.1 to about 5.0 μg/kg/day. For example, when administered orally,treatment with such compounds may comprise administration of aformulations typically containing between about 0.01 μg to about 2000mg, for example between about 0.1 μg to about 500 mg, or between 1 μg toabout 100 mg (e.g. about 20 μg to about 80 mg), of the activeingredient(s). When administered intravenously, the most preferred doseswill range from about 0.001 to about 10 μg/kg/hour during constant rateinfusion. Advantageously, treatment may comprise administration of suchcompounds and compositions in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily (e.g. twice daily with reference to the doses described herein,such as a dose of 10 mg, 20 mg, 30 mg or 40 mg twice daily).

In any event, the physician, or the skilled person, will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the route ofadministration, the type and severity of the condition that is to betreated, as well as the species, age, weight, sex, renal function,hepatic function and response of the particular patient to be treated.The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Preparation of Compounds/Compositions

Pharmaceutical compositions/formulations, combination products and kitsas described herein may be prepared in accordance with standard and/oraccepted pharmaceutical practice.

Thus, in a further aspect of the invention there is provided a processfor the preparation of a pharmaceutical composition/formulation, ashereinbefore defined, which process comprises bringing into associationa compound of the invention, as hereinbefore defined, with one or morepharmaceutically-acceptable adjuvant, diluent or carrier.

In further aspects of the invention, there is provided a process for thepreparation of a combination product or kit-of-parts as hereinbeforedefined, which process comprises bringing into association a compound ofthe invention, as hereinbefore defined, or a pharmaceutically acceptablesalt thereof with the other therapeutic agent that is useful in thetreatment of cancer, and at least one pharmaceutically-acceptableadjuvant, diluent or carrier.

As used herein, references to bringing into association will mean thatthe two components are rendered suitable for administration inconjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

-   (i) provided as separate formulations (i.e. independently of one    another), which are subsequently brought together for use in    conjunction with each other in combination therapy; or-   (ii) packaged and presented together as separate components of a    “combination pack” for use in conjunction with each other in    combination therapy.

Compounds of the invention as described herein may be prepared inaccordance with techniques that are well known to those skilled in theart, such as those described in the examples provided hereinafter.

According to a seventh aspect of the invention there is provided aprocess for the preparation of a compound of the first aspect of theinvention as hereinbefore defined (i.e. a compound of the invention butincluding the proviso), which process comprises:

-   (i) where n represents 2, reaction of a compound of formula IIA

-   wherein R¹, R² and R³ are as defined herein (i.e. for compounds of    the invention, or any particular feature or embodiment thereof) and    LG′ represents a suitable leaving group (such as halo, e.g. chloro),    with a compound of formula IIIA

-   wherein X is as defined herein (i.e. for compounds of the invention,    or any particular feature or embodiments thereof) and M represents    an alkali metal ion (such as a Na ion),-   in the presence of a suitable acid (such as a concentrated acid,    e.g. a concentrated mineral acid, for example concentrated HCl, e.g.    concentrated aqueous HCl) and in the presence of a suitable solvent    (such as a polar organic solvent, e.g. N,N′-dimethylacetamide,    N,N′-dimethylformamide or tetrahydrofuran), and optionally in the    presence of a suitable phase transfer catalyst (such as a quaternary    ammonium salt, e.g. tetra-butyl ammonium chloride);-   (ii) where n represents 2, reaction of a compound of formula IIB

-   wherein R¹, R² and R³ are as defined herein (i.e. for compounds of    the invention, or any particular feature or embodiments thereof) and    M represents an alkali metal ion (such as a Na ion), with a compound    of formula IIIB

-   wherein X is as defined herein in formula I (i.e. for compounds of    the invention, or any particular feature or embodiments thereof) and    LG² represents a suitable leaving group (such as halo, e.g. chloro),    in the presence of a suitable acid (such as a concentrated acid,    e.g. a concentrated mineral acid, for example concentrated HCl, e.g.    concentrated aqueous HCl) and in the presence of a suitable solvent    (such as a polar organic solvent, e.g. N,N′-dimethylacetamide,    N,N′-dimethylformamide or tetrahydrofuran), and optionally in the    presence of a suitable phase transfer catalyst (such as a quaternary    ammonium salt, e.g. tetra-butyl ammonium chloride);-   (iii) where n represents 2, reaction of a compound of formula IIA as    hereinbefore defined with a compound of formula IIIA as hereinbefore    defined, in the presence of a suitable metal halide (such as a    suitable metal iodide, e.g. Cul, or a suitable metal bromide, e.g.    CuBr; which metal halide may be present in excess, such as in amount    corresponding to at least 2 molar equivalents of the compound of    formula IIA and/or the compound of formula IIIA) and in the presence    of a suitable solvent (such as a polar organic solvent, e.g.    N,N′-dimethylacetamide, N,N′-dimethylformamide, tetrahydrofuran or    3-dimethyl-2-imidazolidinone), under conditions known to those    skilled in the art;-   (iv) where n represents 2, reaction of a compound of formula IIB as    hereinbefore defined with a compound of formula IIIB as hereinbefore    defined, in the presence of a suitable metal halide (such as a    suitable metal iodide, e.g. Cul, ora suitable metal bromide, e.g.    CuBr; which metal halide may be present in excess, such as in amount    corresponding to at least 2 molar equivalents of the compound of    formula IIB and/or the compound of formula IIIB) and in the presence    of a suitable solvent (such as a polar organic solvent, e.g.    N,N′-dimethylacetamide, N,N′-dimethylformamide, tetrahydrofuran or    3-dimethyl-2-imidazolidinone), under conditions known to those    skilled in the art;-   (v) reaction of a compound of formula IV

-   wherein R¹ to R³ and X are as defined herein (i.e. for compounds of    the invention, or any particular feature or embodiments thereof),    with a suitable oxidising agent (i.e. an oxidising agent chosen and    used in a manner as required to achieved the desired degree of    oxidation; such as a hypochlorite salt, e.g. sodium hypochlorite, a    peroxymonosulfate salt, e.g. potassium peroxymonosulfate (Oxone), a    percarboxylic acid, e.g. meta-chloroperoxybenzoic acid (mCPBA), or    potassium permanganate) in the presence of a suitable solvent (such    as a polar organic solvent, e.g. N,N′-dimethylacetamide,    N,N′-dimethylformamide or terahydrofuran), and optionally in the    presence of water, under conditions known to those skilled in the    art;-   (vi) where n represents 2, reaction of a compound of formula V

-   wherein R¹, R² and R³ are as defined herein (i.e. for compounds of    the invention, or any particular feature or embodiments thereof) and    LG³ represents a suitable leaving group (such as halo, e.g. chloro)    with a compound of formula VI

-   wherein X is as defined herein (i.e. for compounds of the invention,    or any particular feature or embodiments thereof) and LG⁴ represents    a suitable leaving group (such as a boronic acid), in the presence    of a suitable catalyst (such as a suitable metal halide, e.g. CuBr,    or phenanthroline) and in the presence of a suitable solvent (such    as an organic solvent, e.g. dichloromethane or dichloroethane).

Compounds of formulae IIA, IIB, IIIA, IIIB, IV, V and VI are eithercommercially available, are known in the literature, or may be obtainedeither by analogy with the processes described herein, or byconventional synthetic procedures, in accordance with standardtechniques, from available starting materials using appropriate reagentsand reaction conditions. In this respect, the skilled person may referto inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I.Fleming, Pergamon Press, 1991. Further references that may be employedinclude “Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F.Smith, 3rd edition, published by Chapman & Hall, “ComprehensiveHeterocyclic Chemistry II” by A. R. Katritzky, C. W. Rees and E. F. V.Scriven, Pergamon Press, 1996 and “Science of Synthesis”, Volumes 9-17(Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

In particular, compounds of formula IV may be prepared by reaction of acompound of formula VII

-   wherein X is as defined herein (i.e. for compounds of the invention,    or any particular feature or embodiments thereof), with a compound    of formula IIA as herein before defined, under conditions known to    those skilled in the art, such as in the presence of a suitable base    (such as a metal carbonate, e.g. potassium carbonate, a metal    hydroxide, e.g. sodium hydroxide, or an amine base, e.g. triethyl    amine), and in the presence of a suitable solvent (such as a polar    organic solvent, e.g. N,N′-dimethylacetamide, N,N′-dimethylformamide    or tetrahydrofuran, or a mixture of a polar organic solvent and    water), under conditions known to those skilled in the art.

Similarly, compounds of formula IV may be prepared by reaction of acompound of formula VIII

-   wherein R¹, R² and R³ are as defined herein (i.e. for compounds of    the invention, or any particular feature or embodiments thereof),    with a compound of formula III B as described herein, under    conditions known to those skilled in the art (for example, where the    R⁴ groups present in the compound of formula IIIB are not    sufficiently electron withdrawing, the reaction may be performed in    the presence of a suitable catalyst, such as palladium(II) acetate    or copper oxide, in which case the suitable base may be an alkali    metal tert-butoxide, such as Kt-OBu).

Similarly, compounds of formulae VII and VIII are either commerciallyavailable, are known in the literature, or may be obtained either byanalogy with the processes described herein, or by conventionalsynthetic procedures, in accordance with standard techniques, fromavailable starting materials using appropriate reagents and reactionconditions.

The substituents R¹ to R³ and Y, as hereinbefore defined, may bemodified one or more times, after or during the processes describedabove for preparation of compounds of formula I by way of methods thatare well known to those skilled in the art. Examples of such methodsinclude substitutions, reductions, oxidations, dehydrogenations,alkylations, dealkylations, acylations, hydrolyses, esterifications,etherifications, halogenations and nitrations. The precursor groups canbe changed to a different such group, or to the groups defined informula I, at any time during the reaction sequence. The skilled personmay also refer to “Comprehensive Organic Functional GroupTransformations” by A. R. Katritzky, O. Meth-Cohn and C. W. Rees,Pergamon Press, 1995 and/or “Comprehensive Organic Transformations” byR. C. Larock, Wiley-VCH, 1999.

Compounds of the invention may be isolated from their reaction mixturesand, if necessary, purified using conventional techniques as known tothose skilled in the art. Thus, processes for preparation of compoundsof the invention as described herein may include, as a final step,isolation and optionally purification of the compound of the invention(e.g. isolation and optionally purification of the compound of formulaI).

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be applied and removed in accordance withtechniques that are well known to those skilled in the art and asdescribed hereinafter. For example, protected compounds/intermediatesdescribed herein may be converted chemically to unprotected compoundsusing standard deprotection techniques. The type of chemistry involvedwill dictate the need, and type, of protecting groups as well as thesequence for accomplishing the synthesis. The use of protecting groupsis fully described in “Protective Groups in Organic Synthesis”, 3rdedition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).

In a further aspect of the invention, there is provided a compound offormula IV as defined herein (i.e. wherein R¹, R², R³ and X are asdefined herein, including all particular features and embodimentsthereof), or a pharmaceutically acceptable salt thereof.

Particular compounds of formula IV that may be mentioned include thoseprepared in the examples provided herein, and pharmaceuticallyacceptable salts thereof.

Compounds of the invention may have the advantage that they may be moreefficacious than, be less toxic than, be longer acting than, be morepotent than, produce fewer side effects than, be more easily absorbedthan, and/or have a better pharmacokinetic profile (e.g. higher oralbioavailability and/or lower clearance) than, and/or have other usefulpharmacological, physical, or chemical properties over, compounds knownin the prior art, whether for use in the above-stated indications orotherwise. In particular, compounds of the invention may have theadvantage that they are more efficacious and/or exhibit advantageousproperties in vivo.

Without wishing to be bound by theory, it is thought that inhibition ofthioredoxin reductase is obtained by the utilization of strongelectrophilicity of small molecule inhibitors in combination with apronounced inherent nucleophilicity of NADPH-reduced, but not oxidized,thioredoxin reductase, resulting in selective and potent inhibition ofsaid enzyme without major targeting of other cellular pathways orenzymes.

Moreover, it is thought that normal non-cancerous cells may survivewithout a functional cytosolic thioredoxin reductase enzyme because ofmaintained function of the glutathione system, while cancer cells cannotsurvive upon specific inhibition of cytosolic thioredoxin reductase.

EXAMPLES

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed.

-   aq aqueous-   BSA bovine serum albumin-   conc concentrated-   DMA N,N′-dimethylacetamide-   DMF N,N′-dimethylformamide-   DMSO dimethyl sulfoxide-   DTNB 5,5′-dithid-bis-(2-nitrobenzoic add)-   EDTA ethylenediaminetetraacetic acid-   GSSG glutathione disulfide-   HPLC high performance liquid chromatography-   HRMS high resolution mass spectrometry-   mCPBA meta-chloroperbenzoic acid-   NADPH nicotinamide adenine dinucleotide phosphate-   NMR nuclear magnetic resonance-   PBS phosphate buffered saline-   rt room temperature

Starting materials and chemical reagents specified in the synthesesdescribed below are commercially available from a number of suppliers,such as Sigma Aldrich.

In the event that there is a discrepancy between nomenclature and thestructure of compounds as depicted graphically, it is the latter thatpresides (unless contradicted by any experimental details that may begiven and/or unless it is clear from the context). The names of thefinal compounds may be translated to the structures e.g. usingChemBioDraw Ultra 14.

Example 1: 2-Benzylsulfonyl-6-methoxy-3-nitropyridine

(a) 2-(Benzylthio)-6-methoxy-3-nitropyridine

A mixture of 2-chloro-6-methoxy-3-nitropyridine (0.20 g, 1.06 mmol),benzylmercaptan(0.14 mL, 1.17 mmol), K₂CO₃ (0.18 g, 1.29 mmol) and DMF(1 mL) was stirred at rt for 3 h. The mixture was poured into water andfiltered to give the sub-title compound (0.29 g, 98%).

(b) 2-Benzylsulfonyl-6-methoxy-3-nitropyridine

-   NaOCl (aq, 10%, 1.36 mL, 2.29 mmol) was added dropwise to a stirred    mixture of 2-(benzylthio)-6-methoxy-3-nitropyridine (0.29 g, 1.04    mmol), glacial acetic acid (0.08 mL, 1.34 mmol) and DMF (1 mL) at    rt. The mixture was stirred at rt for 14 h and poured into water.    The pH was adjusted to ˜9 with aq NaOH (20% (w/v)). After stirring    for 5 s the mixture was filtered through a cotton plug and washed    with water. The plug was rinsed with dichloromethane and the    dichloromethane was evaporated to give the title compound as an oil    (0.02 g, 6%).

¹H NMR (400 MHz, CDCl₃) δ8.08-8.04 (1H, m), 7.41-7.30 (5H, m), 7.02-6.98(1H, m), 4.83 (2H, s), 3.97 (3H, s);

¹³C-NMR (100 MHz, CDCl₃) δ163.9, 148.4, 136.2, 131.5, 129.3, 128.9,126.5, 115.7, 60.2, 55.6;

ESI-MS:309 [M+H]⁺.

Example 2: 2-Cyclopentylsulfonyl-6-methoxy-3-nitropyridine

The title compound was prepared in accordance with the procedure inExample 1, Steps (a) and (b) from 2-chloro-6-methoxy-3-nitropyridine andcyclopentylmercaptan. The compound was purified by chromatography.

¹H NMR (400 MHz, CDCl₃) δ□ 8.12-8.07 (1H, m), 7.06-7.00 (1H, m),4.39-4.29 (1H, m), 4.08 (3H, s), 2.25-2.14 (2H, m), 2.08-1.97 (2H, m),1.91-1.80 (2H, m), 1.74-1.62 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ 164.0,149.2, 136.4, 115.4, 77.2, 61.4, 55.5, 27.4, 26.3; ESI-MS:287 [M+H]⁺.

Example 3: 2-Hexylsulfonyl-6-methoxy-3-nitropyridine

The title compound was prepared in accordance with the procedure inExample 1, Steps (a) and (b) from 2-chloro-6-methoxy-3-nitropyridine andhexyl mercaptan.

¹H NMR (400 MHz, CDCl₃) δ 8.16-8.12 (1H, m), 7.07-7.04 (1H, m), 4.08(3H, s), 3.59-3.54 (2H, m), 1.92-1.82 (2H, m), 1.52-1.41 (2H, m),1.36-1.26 (4H, m), 0.92-0.84 (3H, m).

¹³C-NMR (100 MHz, CDCl₃) δ 164.1, 149.2, 136.6, 115.6, 55.6, 55.5, 53.5,31.3, 28.3, 22.4, 22.2, 14.0;

ESI-MS:303 [M+H]⁺.

Example 4: 2-Benzylsulfonyl-6-chloro-3-nitropyridine

(a) 6-Chloro-5-nitropyridin-2-amine

Conc. HNO₃ (2.39 mL, 35.00 mmol) was added dropwise to a mixture of concH₂SO₄ (56 mL, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34mmol) at 0° C. The mixture was stirred at 0° C. for 4 h and poured intoice-water. The mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography to give the sub-title compound(1.38 g, 34%).

(b) 6-(Benzylthio)-5-nitropyridin-2-amine

A mixture of 6-chloro-5-nitropyridin-2-amine (0.26 g, 1.50 mmol),benzylmercaptan (0.19 mL, 1.65 mmol), K₂CO₃ (0.25 g, 1.83 mmol) and DMF(2.1 mL) was stirred at 80° C. for 3.5 h. The mixture was poured intowater and extracted with CH₂Cl₂ (3×15 mL). The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated. The residue wasdissolved in CH₂Cl₂, and the product was precipitated by addition ofhexane to give the sub-title compound (0.32 g, 83%).

(c) 2-(Benzylthio)-6-chloro-3-nitropyridine

Isoamylnitrite (0.30 mL, 2.23 mmol) was added to a stirred mixture of5-nitro-6-(pyridin-2-ylthio)pyridin-2-amine (0.29 g, 1.12 mmol),CuCl₂(0.30 g, 2.24 mmol) and MeCN (5 mL) at rt. The mixture was stirredat 60° C. for 14 h, poured into acidic water (1N HCl, 4 mL) andextracted with EtOAc (3×15 mL). The combined organic layers were washedwith saturated aq NaHCO₃ (10 mL), brine (10 mL) and dried over anhydrousNa₂SO₄ and concentrated. Theresidue was purified by chromatography togive the sub-title compound (0.11 g, 36%).

(d) 2-Benzylsulfonyl-6-chloro-3-nitropyridine

mCPBA (0.11 g, 0.45 mmol) was added in portions to a stirred mixture of6-chloro-3-nitro-2-(pyridin-2-ylthio)pyridine (0.06 g, 0.20 mmol) andCH₂Cl₂ (7 mL) at 0° C. The mixture was stirred at rt for 60 h and pouredinto saturated aq Na₂S₂O₃ (3 mL) at 0° C. The phases were separated andthe organic layer extracted with saturated aq NaHCO₃ (2×5 mL) and brine(5 mL). The combined organic phases were dried over anhydrous Na₂SO₄ andconcentrated. The crude mixture was purified by chromatography to givethe title compound (0.05 g, 71%).

¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz,1H), 7.43-7.41 (m, 2H), 7.37-7.32 (m, 3H), 4.85 (s, 2H).

¹³C-NMR (100 MHz, CDCl₃) δ153.1, 150.0, 144.6, 136.0, 131.7, 129.4,129.1, 129.0, 126.1, 59.7; ESI-MS:313 [M+H]⁺.

Example 5: 6-Chloro-2-(cyclopentylsulfonyl)-3-nitropyridine

The title compound was prepared in accordance with the procedure inExample 4, Steps (a) to (d), from 6-chloropyridin-2-amine andcyclopentylmercaptan

¹H NMR (400 MHz, CDCl₃) δ8.14 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H),4.31 (tt, J=9.0, 6.8 Hz, 1H), 2.21-2.10 (m, 2H), 2.10-1.99 (m, 2H),1.90-1.79 (m, 2H), 1.76-1.63 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃) δ153.2, 150.7, 144.6, 135.9, 128.8, 61.8, 27.3,26.3; ESI-MS:291 [M+H]⁺.

Example 6: 6-Chloro-2-(hexylsulfonyl)-3-nitropyridine

The title compound was prepared in accordance with the procedure inExample 4, Steps (a) to (d), from 6-chloropyridin-2-amine andhexylmercaptan.

¹H NMR (300 MHz, CDCl₃) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H),3.63-3.51 (m, 2H), 1.96-1.79 (m, 2H), 1.55-1.40 (m, 2H), 1.35-1.29 (m,4H), 0.95-0.82 (m, 3H);

¹³C-NMR (75 MHz, CDCl₃) δ 153.4, 150.6, 144.2, 136.1, 129.1, 53.5, 31.2,28.1, 22.4, 22.0, 14.0;

ESI-MS:307 [M+H]⁺.

Example 7: 2-Benzylsulfonyl-6-dimethylamino-3-nitropyridine

(a) 6-Chloro-N,N-dimethylpyridin-2-amine

A mixture of 2,6-dichloropyridine (2.20 g, 14.9 mmol) and DMF (11.5 mL,148.7 mmol) was heated under microwave irradiation at 180° C. for 1 h.The mixture was poured into water and extracted with EtOAc (3×30 mL).The combined organic phases were dried over anhydrous Na₂SO₄ andconcentrated. Theresidue was purified by chromatography to give thesub-title compound (2.12 g, 91%).

(b) 6-Chloro-N,N-dimethyl-5-nitropyridin-2-amine

Conc HNO₃ (0.9 mL, 13.52 mmol) was added dropwise to a mixture of concH₂SO₄ (32.4 mL, 608.6 mmol) and 6-chloro-N,N-dimethylpyridin-2-amine(2.12 g, 13.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1.5 hand poured into ice-water. The mixture was extracted with CH₂Cl₂ (3×100mL). The combined organic layers were washed with saturated aq Na₂CO₃,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby chromatography to give the sub-title compound (0.89 g, 33%).

(c) 6-(Benzylthio)-N,N-dimethyl-5-nitropyridin-2-amine

A mixture of 6-chloro-N,N-dimethyl-5-nitropyridin-2-amine (0.15 g, 0.74mmol), benzylmercaptan(0.10 mL, 0.82 mmol), K₂CO₃ (0.13 g, 0.91 mmol)and DMF (1 mL) was stirred at 80° C. for 1 h. The mixture was pouredinto water, the precipitate was collected, washed with water and driedto give the sub-title compound (0.20 g, 93%).

(d) 6-Dimethylamino-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

mCPBA (0.36 g, 1.52 mmol) was added in portions to a stirred mixture of6-(benzylthio)-N,N-dimethyl-5-nitropyridin-2-amine (0.20 g, 0.69 mmol)and CH₂Cl₂ (8 mL) at 0° C. The mixture was stirred at rt for 5 h andpoured into saturated aq K₂CO₃ (5 mL). The phases were separated and theaq layer extracted with CH₂Cl₂. The combined organic phases were washedwith saturated aq Na₂S₂O₅ and NaHSO₃ mixture, dried over anhydrousNa₂SO₄ and concentrated. The residue was recrystallized from H₂O/EtOH(1:9) to give the title compound (0.15 g, 69%).

¹H NMR (400 MHz, CDCl₃) δ8.09 (1H, d, J=9.3 Hz), 7.47-7.41 (2H, m),7.37-7.32 (3H, m), 6.58 (1H, d, J=9.3 Hz), 4.87 (2H, s), 3.20 (6H, 5);

¹³C-NMR (100 MHz, CDCl₃) δ 158.0, 151.6, 135.8, 131.8, 129.0, 128.8,127.1, 107.4, 59.3, 38.7;

ESI-MS:332 [M+H]⁺.

Example 8: 2-Cyclopentylsulfonyl-6-dimethylamino-3-nitropyridine

The title compound was prepared in accordance with the procedure inExample 7, Steps (a) to (d), from 2,6-dichloropyridine andcyclopentylmercaptan. The compound did not precipitate and was insteadpurified by chromatography.

¹H NMR (400 MHz, CDCl₃) δ8.09 (1H, d, J=9.3 Hz), 6.59 (1H, d, J=9.3 Hz),4.44 (1H, tt, J=9.1, 6.7 Hz), 3.23 (6H, s), 2.21-2.11 (2H, m), 2.09-1.98(2H, m), 1.89-1.78 (2H, m), 1.71-1.59 (2H, m);

¹³C-NMR (100 MHz, CDCl₃) δ 158.0, 151.9, 135.8, 107.1, 60.8, 38.6, 27.7,26.3; ESI-MS:300 [M+H]⁺.

Example 9: 6-Dimethylamino-2-hexylsulfonyl-3-nitropyridine

The title compound was prepared in accordance with the procedure inExample 7, Steps (a) to (d), from 2,6-dichloropyridine andhexylmercaptan. The compound did not precipitate and was insteadpurified by chromatography.

¹H NMR (400 MHz, CDCl₃) δ8.13 (1H, d, J=9.4 Hz), 6.61 (1H, d, J=9.3 Hz),3.61-3.56 (2H, m), 3.23 (6H, s), 1.94-1.84 (2H, m), 1.51-1.40 (2H, m),1.36-1.27 (4H, m), 0.91-0.84 (3H, m);

¹³C-NMR (100 MHz, CDCl₃) δ 158.1, 151.9, 136.0, 107.3, 53.3, 38.7, 31.4,28.5, 22.5, 22.5, 14.1;

ESI-MS:316 [M+H]⁺.

The following example compounds where prepared from2-chloro-6-methoxy-3-nitropyridine and the appropriate alkylthiol inaccordance with the procedure in Example 1, Step a, and Example 4, Stepd.

Chemical structure Name Ex. ¹H-NMR [solvent, δ] MS [m/z (M + H)⁺] 10

MS [m/z (M + H)⁺ = (Calculated for C₈H₁₀N₂O₅S + H: 247.04) found: 247.1]2-(ethylsulfonyl)-6-methoxy-3-nitropyridine ¹H-NMR [DMSO-d₆, δ 8.48 (d,J = 9 Hz, 1H), 7.36 (d, J = 9 Hz, 1H), 4.02 (s, 3H), 3.72-3.67 (m, 2H),1.26 (t, J = 7 Hz, 3H)] 11

MS [m/z (M + H)⁺ = (Calculated for C₉H₁₂N₂O₅S + H: 261.06) found: 261.1]2-(isopropylsulfonyl)-6-methoxy- 3-nitropyridine ¹H-NMR [CDCl₃, δ 8.04(d, J = 9 Hz, 1H), 7.03 (d, J = 9 Hz, 1H), 4.07-4.06 (m, 4H), 1.43 (d, J= 7 Hz, 6H)] 12

MS [m/z (M + H)⁺ = (Calculated for C₁₄H₂₂N₂O₅S + H: 331.13) found:331.2] 6-methoxy-3-nitro-2-(octylsulfonyl)pyridine ¹H-NMR [CDCl₃, δ 8.13(d, J = 9 Hz, 1H), 7.04 (d, J = 8 Hz, 1H), 4.07 (s, 3H), 3.56 (t, J = 8Hz, 2H), 1.89-1.86 (m, 2H), 1.46-1.44 (m, 2H), 1.27-1.25 (m, 8H), 0.86(m, 3H)] 13

MS [m/z (M + H)⁺ = (Calculated for C₉H₁₀N₃O₅S + H: 259.04) found: 259.1]2-(cyclopropylsulfonyl)-6-methoxy- 3-nitropyridine ¹H-NMR [DMSO-d₆, δ8.48 (d, J = 9 Hz, 1H), 7.35 (d, J = 9 Hz, 1H), 4.04 (s, 3H), 3.27-3.23(m, 1H), 1.24-1.22 (m, 2H), 1.16-1.15 (m, 2H)] 14

MS [m/z (M + H)⁺ = (Calculated for C₁₁H₁₃F₃N₂O₅S + H: 343.06) found:342.8] 6-methoxy-3-nitro-2-((5,5,5-trifluoropentyl) sulfonyl)pyridine¹H-NMR [DMSO-d₆, δ 8.48 (d, J = 9 Hz, 1H), 7.37 (d, J = 9 Hz, 1H), 4.02(s, 3H), 3.76 (t, J = 8 Hz, 2H), 2.34-2.24 (m, 2H), 1.78-1.77 (m, 2H),1.65-1.63 (m, 2H)] 15

MS [m/z (M + H)⁺ = (Calculated for C₁₀H₁₃N₂O₆S + H: 304.06) found:304.2] N-(2-((6-methoxy-3-nitropyridin-2- yl)sulfonyl)ethyl)acetamide¹H-NMR [DMSO-d₆, δ 8.48 (d, J = 9 Hz, 1H), 8.06-8.04 (m, 1H), 7.35 (d, J= 9 Hz, 1H), 4.05 (s, 3H), 3.86 (t, J = 7 Hz, 2H), 3.45 (q, J = 7 Hz,2H), 1.69 (s, 3H)] 16

MS [m/z (M + H)⁺ = (Calculated for C₁₀H₁₂N₂O₇S + H: 305.05) found:305.1] methyl 3-((6-methoxy-3-nitropyridin-2- yl)sulfonyl)propanoate¹H-NMR [DMSO-d₆, δ 8.49 (d, J = 9 Hz, 1H), 7.37 (d, J = 9 Hz, 1H), 4.01-3.97 (m, 5H), 3.59 (s, 3H), 2.84 (t, J = 7 Hz, 2H)] 17

MS [m/z (M + H)⁺ = (Calculated for C₉H₁₂N₂O₆S + H: 277.05) found: 277.1]3-((6-methoxy-3-nitropyridin-2-yl) sulfonyl)propan-1-ol ¹H-NMR [CDCl₃, δ8.15 (d, J = 9 Hz, 1H), 7.05 (d, J = 9 Hz, 1H), 4.08 (s, 3H), 3.85-3.73(m, 4H), 2.17-2.14 (m, 2H), 1.61-1.58 (m, 1H)] 18

MS [m/z (M + H)⁺ = (Calculated for C₁₃H₁₉N₃O₅S + H: 330.11) found:330.2] 6-methoxy-3-nitro-2-((2-(piperidin-1- yl)ethyl)sulfonyl)pyridine¹H-NMR [CDCl₃, δ 8.07 (d, J = 9 Hz, 1H), 7.03 (d, J = 9 Hz, 1H), 4.09(s, 3H), 3.76 (t, J = 7 Hz, 2H), 285 (t, J = 7 Hz, 2H), 2.31 (broad s,4H), 1.27 (broad s, 6H)] 19

MS [m/z (M + H)⁺ = (Calculated for C₁₃H₁₁ClNO₅S + H: 343.02) found:342.8] 2-((2-chlorobenzyl)sulfonyl)-6- methoxy-3-nitropyridine ¹H-NMR[DMSO-d₆, δ 8.48 (d, J = 9 Hz, 1H), 7.55 − 7.37 (m, 5H), 5.19 (s, 2H),3.94 (s, 3H)] 20

MS [m/z (M + H)⁺ = (Calculated for C₁₃H₁₁ClN₂O₅S + H: 343.02) found:343.0] 2-((3-chlorobenzyl)sulfonyl)-6- methoxy-3-nitropyridine ¹H-NMR[DMSO-d₆, 8.46 (d, J = 9 Hz, 1H), 7.49-7.28 (m, 5H), 5.11 (s, 2H), 4.05(s, 3H)] 21

MS [m/z (M + H)⁺ = (Calculated for C₁₃H₁₁ClN₂O₅S + H: 343.02) found:343.0] 2-((4-chlorobenzyl)sulfonyl)-6-methoxy- 3-nitropyridine ¹H-NMR[CDCl₃, δ 8.09 (d, J = 9 Hz,1H), 7.33 (s, 4H), 7.02 (d, J = 9 Hz, 1H),4.79 (s, 2H), 4.00 (s, 3H)] 22

MS [m/z (M + H)⁺ = (Calculated for C₁₃H₁₁ClN₂O₅S + H: 327.05) found:327.0] 2-((4-fluorobenzyl)sulfonyl)-6-methoxy- 3-nitropyridine ¹H-NMR[CDCl₃, δ 8.09 (d, J = 9 Hz, 1H), 7.42-7.37 (m, 2H), 7.08-6.98 (m, 3H),4.79 (s, 2H), 4.00 (s, 3H)] 23

MS [m/z (M + H)⁺ = (Calculated for C₁₄H₁₄N₂O₅S + H: 323.07) found:323.2] 6-methoxy-2-((4-methylbenzyl)sulfonyl)- 3-nitropyridine ¹H-NMR[CDCl₃, δ 8.06 (d, J = 9 Hz, 1H), 7.28-7.24 (m, 2H), 7.13 (d, J = 8 Hz,2H), 6.99 (d, J = 9 Hz, 1H), 4.78 (s, 2H), 3.99 (s, 3H), 2.32 (s, 3H)]24

MS [m/z (M + H)⁺ = (Calculated for C₁₄H₁₄N₂O₆S + H: 339.07) found:339,2] 6-methoxy-2-((4-methoxybenzyl)sulfonyl)- 3-nitropyridine ¹H-NMR[CDCl₃, δ 8.08 (d, J = 9 Hz, 1H), 7.30 (d, J = 8 Hz, 2H), 6.99 (d, J = 9Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 4.77 (s, 2H), 4.01 (s, 3H), 3.79 (s,3H)] 25

MS [m/z (M + H)⁺ = (Calculated for C₁₄H₁₁F₃N₂O₆S + H: 393.04) found:392.8] 6-methoxy-3-nitro-2-((4-(trifluoromethoxy)benzyl)sulfonyl)pyridine ¹H-NMR [DMSO-d₆, δ 8.46 (d, J = 9 Hz, 1H),7.50-7.46 (m, 3H), 7.43-7.35 (m, 3H), 5.13 (s, 2H), 4.03 (s, 3H)] 26

MS [m/z (M + H)⁺ = (Calculated for C₁₄H₁₄N₂O₅S + H: 323.07) found:323.1] 6-methoxy-3-nitro-2- (phenethylsulfonyl)pyridine ¹H-NMR [CDCl₃, δ8.11 (d, J = 9 Hz, 1H), 7.30-7.15 (m, 5H), 7.00 (d, J = 9 Hz, 1H), 4.03(s, 3H), 3.90-3.86 (m, 2H), 3.22-3.18 (m, 2H)] 27

MS [m/z (M + H)⁺ = (Calculated for C₁₅H₁₆N₂O₅S + H: 337.07) found:337.1] 6-methoxy-3-nitro-2-((3-phenylpropyl) sulfonyl)pyridine ¹H-NMR[DMSO-d₆, δ 8.46 (d, J = 9 Hz, 1H), 7.34 (d, J = 9 Hz, 1H), 7.32 - 7.15(m, 5H), 3.90 (s, 3H), 3.67 (t, J = 7 Hz, 2H), 2.73 (t, J = 7 Hz, 2H)1.99-1.95 (m, 2H)] 28

MS [m/z (M + H)⁺ = (Calculated for C₁₄N₁₄N₂O₆S + H: 339.07) found:338.8] 6-methoxy-3-nitro-2-((2-phenoxyethyl) sulfonyl)pyridine ¹H-NMR[CDCl₃, δ 8.15 (d, J = 9 Hz, 1H), 7.21 (d, J = 8 Hz, 2H), 7.02 (d, J = 9Hz, 1H), 6.95 (t, J = 7 Hz, 1H), 6.62 (d, J = 8 Hz, 2H), 4.50 (t, J = 6Hz, 2H), 4.10 (t, J = 6 Hz, 2H), 3.87 (s, 3H)] 29

MS [m/z (M + H)⁺ = (Calculated for C₁₁H₁₀N₂O₆S + H: 299.04) found:299.0] 2-((furan-2-ylmethyl)sulfonyl)-6- methoxy-3-nitropyridine ¹H-NMR[CDCl₃, δ 8.13 (d, J = 9 Hz, 1H), 7.36 (s, 1H), 7.02 (d, J = 9 Hz, 1H),6.48 (s, 1H), 6.35 (s, 1H), 4.96 (s, 2H), 4.07 (s, 3H)] 30

MS [m/z (M + H)⁺ = (Calculated for C₁₂H₁₂N₄O₅S + H: 325.06) found:325.1] 2-(2-((6-methoxy-3-nitropyridin-2- yl)sulfonyl)ethyl)pyrazine¹H-NMR [DMSO-d₆, δ 8.62 (s, 1H), 8.53- 8.50 (m, 1H), 8.49-8.46 (m, 2H),7.33 (d, J = 9 Hz, 1H), 4.20 (t, J = 7 Hz, 2H), 3.99 (s, 3H), 3.32-3.27(m, 2H)]

Example 31: 2-Ethanesulfinyl-6-methoxy-3-nitro-pyridine

(a) 2-Ethanesulfanyl-6-methoxy-3-nitro-pyridine

To a solution of 6-methoxy-2-chloro-3-nitro pyridine (5 g, 26.59 mmol)in dimethylformamide (50 mL) was added potassium carbonate (4.44 g,31.95 mmol) and ethane thiol (1.81 g, 29.25 mmol) at room temperature.The reaction mixture was stirred overnight at room temperature. Progressof reaction was monitored by LCMS. The reaction mixture was quenchedwith ice cold water (35 mL) where in solid precipitated from thereaction mixture. The solid were filtered and washed with ice cold water(3×30 mL) and was dried under reduced pressure affording the thesub-title compound as a yellow solid (4.8 g, 84.24%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.49 (d, J=9.0 Hz, 1H), 6.75 (d, J=9.0 Hz,1H), 4.04 (s, 3H), 3.21 (q, J=7.3 Hz, 2H), 1.34 (t, J=7.3 Hz, 3H);

LCMS [m/z (M+H)⁺] 215 (MW calc=214) R_(t)=1.69

(b) 2-Ethanesulfinyl-6-methoxy-3-nitro-pyridine

To a solution of the compound obtained from step (a) (4.8 g, 22.42 mmol)in dichloromethane (100 mL) was added m-chloro per benzoic acid (8.84 g,51.40 mmol) at room temperature. The reaction mixture was stirred atroom temperature overnight. Progress of reaction was monitored by LCMS.The reaction mixture was diluted with dichloromethane (20 mL) and washedwith saturated sodium sulphite solution (2×80 mL) followed by brine(1×80 mL). The organic layer was dried over anhydrous sodium sulphateand was evaporated under reduced pressure to give the crude productwhich was purified by column chromatography eluting with 80% ethylacetate in hexane affording the title compound as a yellow solid (2.6 g,60.61%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.55 (d, J=8.9 Hz, 1H), 7.16 (d, J=8.9 Hz,1H), 4.08 (s, 3H), 3.26-3.18 (m, 1H), 2.97-2.88 (m, 1H), 1.23 (t, J=7.3Hz, 3H) MS [m/z (M+H)⁺] 231 (MW calc=230), R_(t)=1.66

HPLC purity at λ=220 nm: 99.38%.

Example 32: 2-Benzylsufinyl-6-methoxy-3-nitro-pyridine

(a) 2-Benzylsulfanyl-6-methoxy-3-nitro-pyridine

To a solution of 6-methoxy-2-chloro-3-nitro pyridine (5.0 g, 26.59 mmol)in dimethylformamide (20 mL) was added potassium carbonate (4.441 g,32.181 mmol) and benzyl mercaptan (3.595 g, 28.98 mmol) at roomtemperature. The reaction mixture was stirred for overnight at roomtemperature. Progress of reaction was monitored by LCMS. The reactionmixture was quenched with ice cold water (30 mL) and was extracted withethyl acetate (300 mL). The organic layer was washed with water (3×50mL) followed by brine (1×50 mL). The organic layer was dried overanhydrous sodium sulphate and was evaporated under reduced pressure togive the crude product which was purified by column chromatographyeluting with 2% ethyl acetate in hexane affording the sub-title compoundas pale yellow solid (3.2 g, 43.55%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.51 (d, J=8.96 Hz, 1H), 7.44 (d, J=7.3 Hz,2H), 7.34 (t, J=7.4 Hz, 2H), 7.29-7.26 (m, 1H), 6.77 (d, J=8.96 Hz, 1H),4.52 (s, 2H), 4.01 (s, 3H); LCMS [m/z (M+H)⁺] 277 (MW calc=276);R_(t)=1.83

(b) 2-Benzylsufinyl-6-methoxy-3-nitro-pyridine

To a solution of 2-benzylsulfanyl-6-methoxy-3-nitro-pyridine (2.0 g,72.46 mmol) in dichloromethane (30 mL) was added m-chloro per benzoicacid (1.87 g, 10.87 mmol) at room temperature. The reaction mixture wasstirred at room temperature for overnight. Progress of reaction wasmonitored by LCMS. The reaction mixture was diluted with dichloromethane(15 mL) and washed with saturated sodium sulphite solution (2×10 mL)followed by brine (1×20 mL). The organic layer was dried over anhydroussodium sulphate and was evaporated under reduced pressure to give thecrude product which was purified by column chromatography eluting with40% ethyl acetate in hexane affording the title compound as yellow solid(2.0 g, 94.42%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.56 (d, J=8.9 Hz, 1H), 7.33-7.31 (m, 3H),7.21-7.20 (m, 2H), 7.13 (d, J=8.96 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H),4.09 (d, J=12.8 Hz, 1H), 3.90 (s, 3H);

LCMS [m/z (M+H)⁺] 293 (MW calc=292); R_(t)=1.74;

HPLC purity at λ=220 nm: 98.98%.

Example 33: 6-Methoxy-3-nitro-2-octylsulfinyl-pyridine

(a) 6-Methoxy-3-nitro-2-octylsulfanyl-pyridine

To a solution of 6-methoxy-2-chloro-3-nitro pyridine (10 g, 53.191 mmol)in dimethylformamide (50 mL) was added potassium carbonate (8.8 g,63.829 mmol) and octane-1-thiol (8.54 g, 58.51 mmol) at roomtemperature. The reaction mixture was stirred for 12 hours at roomtemperature. Progress of reaction was monitored by LCMS. The reactionmixture was quenched with ice cold water (100 mL) and was extracted withethyl acetate (200 mL). The organic layer was washed with water (3×75mL) followed by brine (1×50 mL). The organic layer was dried overanhydrous sodium sulphate and was evaporated under reduced pressure togive the crude product which was purified by column chromatographyeluting with 10% ethyl acetate in hexane affording the sub-titlecompound as yellow solid (13 g, 82%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.48 (d, J=9.0 Hz, 1H), 6.74 (d, J=9.0 Hz,1H), 4.02 (s, 3H), 3.18 (t, J=7.4 Hz, 2H), 1.75-1.65 (m, 2H), 1.42-1.35(m, 2H), 1.3-1.2 (m, 8H), 0.86-0.83 (m, 3H);

¹³C NMR (DMSO-d₆, 100 MHz) δ 164.0, 158.0, 137.3, 135.8, 106.4, 54.5,31.1, 30.0, 28.57, 28.52, 28.38, 21.9, 13.8;

LCMS [m/z (M+H)⁺] 299 (MW calc=298) R_(t)=2.12

(b) 6-Methoxy-3-nitro-2-octylsulfinyl-pyridine

To a solution of 6-methoxy-3-nitro-2-octylsulfanyl-pyridine (600 mg,2.013 mmol) in dichloromethane (10 mL) was added m-chloro per benzoicacid (519 mg, 3.020 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 4 hours. Progress of reaction was monitored byLCMS. The reaction mixture was quenched with sodium sulphite and sodiumbicarbonate (1:1) solution for 20 minutes. The reaction mixture wasextracted with dichloromethane (3×30 mL) and combined organic layer waswashed with brine (1×20 mL). The organic layer was separated and driedover anhydrous sodium sulphate and was evaporated under reduced pressureto give the crude product which was purified by column chromatographyeluting with 50% ethyl acetate in hexane affording the title compound asbrown sticky liquid (430 mg, 68%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.54 (d, J=8.9 Hz, 1H), 7.15 (d, J=8.9 Hz,1H), 4.08 (s, 3H), 3.20-3.13 (m, 1H), 2.87-2.81 (m, 1H), 1.86-1.79 (m,1H), 1.70-1.67 (m, 1H), 1.45-1.40 (m, 2H), 1.29-1.21 (m, 8H), 0.88-0.81(m, 3H);

¹³C NMR (DMSO-d₆, 100 MHz) δ 165.8, 161.6, 137.2, 136.8, 112.5, 55.1,53.8, 31.0, 28.44, 28.4, 27.7, 22.4, 21.9, 13.7;

MS [m/z (M+H)⁺] 315 (MW calc=314); R_(t)=1.92;

HPLC purity at λ=220 nm: 99.80%.

Biological Examples Biological Example 1: Inhibition of RecombinantTrxR1 and GR

Small molecule inhibition of recombinant thioredoxin reductase 1 (TrxR1)and gluthathione reductase (GR) was examined in 96-well plate format. 30nM TrxR1 was incubated in the presence of 250 μM NADPH, 0.1 mg/ml BSA,and various concentrations of compound (1% DMSO final) in 50 mM Tris (pH7.5) and 2 mM EDTA buffer for 15 minutes. Following the incubationperiod, 2 mM DTNB was added to each well and the change in O.D. at 412nm was followed. Percent activity was determined using DMSO vehicle andno TrxR1 (blank) controls. 2 nM GR was incubated in the presence of 250μM NADPH, 0.1 mg/ml BSA, and various concentrations of compounds (1%DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA buffer for 15 minutes.Following the incubation period, 1 mM GSSG was added to each well andthe change in O.D. at 340 nm was followed. Percent activity wasdetermined using DMSO vehicle and no GR (blank) controls.

Using the assays described in Biological Example 1, the following IC₅₀values were obtained. The results obtained are provided in Table 1below.

Example TrxR Assay IC50 GR Assay IC50 # (nM) (μM) 1 18.2 >100 μM 21030 >100 μM 3 489 >100 μM 4 39.2 18.1 5 181 60.5 6 56.0  8.76 7276 >100 μM 8 188 >100 μM 9 333 >100 μM 10 124 >100 μM 11 204 >100 μM 1212.3 >100 μM 13 160 >100 μM 14 96.9 >100 μM 15 122 >100 μM 16 60.6 >100μM 17 103 >100 μM 18 1.52 >100 μM 19 7.60 >100 μM 20 7.16 >100 μM 214.35 >100 μM 22 5.05 >100 μM 23 14.51 >100 μM 24 25.3 >100 μM 251.03 >100 μM 26 18.8 >100 μM 27 7.33 >100 μM 28 20.3 >100 μM 296.78 >100 μM 30 66.9 >100 μM 31 131.3 >100 μM 32 76.5 — 33 500 85.4

Biological Example 2: Head and Neck Cancer Cell Viability Assay

FaDu cells were plated 2000 cells/well in 96-well black optical platesin the presence of 10% FBS media containing 25 nM selenite. Thefollowing day cells were treated with various concentrations of thecompound of Example 1 (0.1% DMSO final) and incubated for 72 hrs. Afterthe incubation Cell-Quanti Blue reagent was added to each well andincubated for additional 3 hrs. Fluorescence was read ex:530 nm/em:590nm, and percent of viability was determined using DMSO vehicle and nocell (blank) controls.

Using the assays described in Biological Example 2, the following IC₅₀values were obtained. The results obtained are provided in Table 2below.

FaDu Cell IC50 Example # (μM) 1 0.28 2 3.65 3 0.45 4 0.66 5 1.01 6 0.717 2.88 8 6.97 9 12.69

Biological Example 3: Breast Cancer Cell Viability Assay

MDA-MB-231 cells were plated 2000 cells/well in 96-well black opticalplates in the presence of 10% FBS media containing 25 nM selenite. Thefollowing day cells were treated with various concentrations ofcompounds (0.1% DMSO final) and incubated for 72 hrs. After theincubation Alamar Blue reagent was added to each well and incubated foradditional 3 hrs. Fluorescence was read ex:530 nm/em:590 nm, and percentof viability was determined using DMSO vehicle and no cell (blank)controls.

Using the assays described in Biological Example 3, the following IC₅₀values were obtained. The results obtained are provided in Table 3below.

MDA-MB-231 Example Cell viability # IC50 (μM) 1 3.81 10 2.95 12 4.51 145.6 15 11.36 16 8.09 17 12.46 19 1.8 20 3.2 21 4.1 22 1.85 24 3.5 265.22 27 7.13 28 5.24 29 4.36 30 2.66

Biological Example 4: Cancer Cell Viability Assay

Breast cancer and glioblastoma cell lines were plated 4000 cells/well in96-well plates in the presence of 10% FBS media. The following day cellswere treated with various concentrations of the example compounds (0.1%DMSO final) and incubated for 72 hrs.

After the incubation An MTT assay was performed to access cellviability. Percent of viability was determined using DMSO vehicle and nocell (blank) controls.

Using the assays described in Biological Example 4, the following IC₅₀values were obtained. The results obtained are provided in Table 4below.

U-87 MG MDA-MB-231 MDA-MB-468 IC50 IC50 IC50 Example # (μM) (μM) (μM) 16.11 1.8 2.89 10 5.95 5.12 3.16 11 6 7.1 4.9 13 6.92 5.91 4.68 14 7.527.73 3.88 15 16.27 18.4 5.47 16 5.23 4.9 3.9 17 19.53 >33 μM 9.77 316.22 3.51 3.23 32 2.48 1.42 0.64 33 9.25 3.84 1.85

Biological Example 5: In Vivo Mouse Study

Athymic nude mice were inoculated orthotopically with 5×10⁶ MDA-MB-231breast cancer cells into the mammary fat pad, and randomized fortreatment when tumors reached an average volume of 80-120 mm³ (N=12 ineach group).

Mice were either treated with 25 mg/kg of the compound of Example 10 viaintraveneous injection (IV) or intraperitoneal injection (IP), or withvehicle alone by intravenous injection, once a day for the first fivedays, followed by two days of no treatment, then three times per weekfor two weeks and four days totaling 12 doses.

Xenograft tumor volume was assessed using caliper measurements for 25days. The results obtained are provided in FIG. 1.

Biological Example 6: In Vivo Mouse Study

Athymic nude mice were inoculated orthotopically with 5×10⁶ MDA-MB-231breast cancer cells into the mammary fat pad, and randomized fortreatment when tumors reached an average volume of 80-120 mm³ (N=12 ineach group).

Mice were either treated with 10 mg/kg of the compound of Example 10, 10mg/kg of the compound of Example 12, or 5 mg/kg of the compound ofExample 31 via intravenous, injection, or with the respective vehiclevia intraveneous injection, once a day using a 5 day on, two day off(5/2) dosing regimen for the duration of the experiment.

Xenograft tumor volume was assessed using caliper measurements for 25days. The results obtained are provided in FIG. 2.

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: L represents—S(O)_(n)—; n represents 2 or 1; X represents C₁₋₁₂ alkyl, C₂₋₁₂ alkenylor C₂₋₁₂ alkynyl each optionally substituted by one or more groupsindependently selected from Y; R¹ represents halo, —N(R^(j1))R^(k1),—OR^(l1) or —SR^(m1); R² and R³ each independently represent H, halo,R^(a1), —CN, -A^(a1)-C(Q^(a1))R^(b1), -A^(b1)-C(Q^(b1))N(R^(c1))R^(d1),-A^(c1)-C(Q^(c1))OR^(e1), -A^(d1)-S(O)_(p)R^(f1),-A^(e1)-S(O)_(p)N(R^(g1))R^(h1), -A^(f1-)-S(O)_(p)OR^(i1), —N₃,—N(R^(j1))R^(k1), —N(H)CN, —NO₂, —ONO₂, —OR^(l1) or —SR^(m1), eachA^(a1) to A^(f1) independently represents a single bond, —N(R^(p1))— or—O—; each Q^(a1) to Q^(c1) independently represents ═O, ═S, ═NR^(a1) or═N(OR^(o1)); each R^(a1) and R^(f1) independently represents C₁₋₆ alkyl,C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by one or moregroups independently selected from G^(1a), heterocyclyl optionallysubstituted by one or more groups independently selected from G^(1b),aryl optionally substituted by one or more groups independently selectedfrom G^(1c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(1d); each R^(b1), R^(c1), R^(d1), R^(e1),R^(g1), R^(h1), R^(i1), R^(j1), R^(k1), R^(l1), R^(m1), R^(n1), R^(o1)and R^(p1) independently represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more groups independentlyselected from G^(1a), heterocyclyl optionally substituted by one or moregroups independently selected from G^(1b), aryl optionally substitutedby one or more groups independently selected from G^(1c), or heteroaryloptionally substituted by one or more groups independently selected fromG^(1d); any of R^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) andR^(k1) are linked together to form, together with the nitrogen atom towhich they are attached, a 3- to 6-membered ring, which ring optionallycontains one further heteroatom and which ring optionally is substitutedby one or more groups independently selected from G^(1b), C₁₋₃ alkyl,C₂₋₃ alkenyl or C₂₋₃ alkynyl each optionally substituted by one or moreG^(1a), and ═O; each G^(1a) and G^(1b) independently represents halo,—CN, —N(R^(a2))R^(b2), —OR^(c2), —SR^(d2) or ═O; each R^(a2), R^(b2),R^(c2) and R^(d2) independently represents H, or C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl each optionally substituted by one or morefluoro; or R^(a2) and R^(b2) are linked together to form, along with thenitrogen atom to which they are attached, a 3- to 6-membered ring, whichring optionally contains one further heteroatom and which ringoptionally is substituted by one or more groups independently selectedfrom fluoro and C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl each optionallysubstituted by one or more fluoro; each Y independently represents halo,R^(a3), —CN, -A^(a2)-(Q^(a2))R^(b3), -A^(b2)-(Q^(b2))N(R^(c3))R^(d3),-A^(c2)-(Q^(c2))OR^(e3), -A^(d2)-S(O)_(q)R^(f3),-A^(e2)-S(O)_(q)N(R^(g3))R^(h3), -A^(f2)-S(O)_(q)OR^(i3), —N₃,—N(R^(j3))R^(k3), —N(H)CN, —NO₂, —ONO₂, —OR^(l3), —SR^(m2) or ═O; eachQ^(a2) to Q^(c2) independently represents ═O, ═S, ═NR^(a3) or═N(OR^(o3)); each A^(a2) to A^(f2) independently represents a singlebond, —N(R^(p3))— or —O—; each R^(a3) independently representsheterocyclyl optionally substituted by one or more groups independentlyselected from G^(2b), aryl optionally substituted by one or more groupsindependently selected from G^(2c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(2d); each R^(f3)independently represents C₁₋₆ alkyl optionally substituted by one ormore groups independently selected from G^(2a), heterocyclyl optionallysubstituted by one or more groups independently selected from G^(2b),aryl optionally substituted by one or more groups independently selectedfrom G^(2c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(2d); each R^(b3), R^(c3), R^(d3), R^(e3),R^(g3), R^(h3), R^(i3), R^(j3), R^(k3), R^(l3), R^(m3), R^(n3), R^(o3)and R^(p3) independently represents H, C₁₋₆ alkyl optionally substitutedby one or more groups independently selected from G^(2a), heterocyclyloptionally substituted by one or more groups independently selected fromG^(2b), aryl optionally substituted by one or more groups independentlyselected from G^(2c), or heteroaryl optionally substituted by one ormore groups independently selected from G^(2d); or any two R^(c3) andR^(d3), R^(g3) and R^(h3) and/or R^(j3) and R^(k3) are linked togetherto form, along with the nitrogen atom to which they are attached, a 3-to 6-membered ring, which ring optionally contains one furtherheteroatom and which ring optionally is substituted by one or moregroups independently selected from heterocyclyl optionally substitutedby one or more groups independently selected from G^(2b), aryloptionally substituted by one or more groups independently selected fromG^(2c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(2d), and ═O; each G^(2a) independentlyrepresents halo, —CN, —N(R^(j4))R^(k4); —OR^(l4); —SR^(m4) or ═O; eachG^(2b) independently represents halo, R^(a4), —CN, —N(R^(j4))R^(k4);—OR^(l4); —SR^(m4) or ═O; each G^(2c) and G^(2d) independentlyrepresents halo, R^(a4), —CN, -A^(a3)-(Q^(a4))R^(b4),-A^(b3)-C(Q^(b3))N(R^(c4))R^(d4), -A^(c3)-C(Q^(c3))OR^(e4),-A^(d3)-S(O)_(q)R^(f4), -A^(e3)-S(O)_(q)N(R^(g4))R^(h4),-A^(f3)-S(O)_(q)OR^(i4), —N₃, —N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂,—OR^(l4) or —SR^(m4); each Q^(a3) to Q^(c3) independently represents ═O,═S, ═NR^(n4) or ═N(OR^(o4)); each A^(a3) to A^(f3) independentlyrepresents a single bond, —N(R^(p4))— or —O—; each R^(a4) and R^(f4)independently represents C₁₋₆ alkyl optionally substituted by one ormore groups independently selected from G^(3a), heterocyclyl optionallysubstituted by one or more groups independently selected from G^(3b),aryl optionally substituted by one or more groups independently selectedfrom G^(3c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(3d); each R^(b4), R^(c4), R^(d4), R^(e4),R^(g4), R^(h4), R^(i4), R^(k4), R^(l4), R^(m4), R^(n4), R^(o4) and—R^(p4) independently represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more groups independentlyselected from G^(3a) or heterocyclyl optionally substituted by one ormore groups independently selected from G^(3b), aryl optionallysubstituted by one or more groups independently selected from G^(3c), orheteroaryl optionally substituted by one or more groups independentlyselected from G^(3d); or any of R^(c4) and R^(d4), R^(g4) and R^(h4)and/or R^(j4) and R^(k4) are linked together to form, together with thenitrogen atom to which they are attached, a 3- to 6-membered ring, whichring optionally contains one further heteroatom and which ringoptionally is substituted by one or more groups independently selectedG^(3b); each G^(3a) and G^(3b) independently represents halo, R^(a5),—CN, —N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O; each R^(a5)independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl eachoptionally substituted by one or more groups independently selected fromG⁴; each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H,or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substitutedby one or more groups independently selected from G⁴; or each R^(b5) andR^(c5) are linked together to form, together with the nitrogen atom towhich they are attached, a 3- to 6-membered ring, which ring optionallycontains one further heteroatom and which ring optionally is substitutedby one or more groups independently selected from G⁴; each G⁴independently represents halo, R^(a6), —CN, —N(R^(b6))R^(c6); —OR^(d6)or ═O; each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl each optionally substituted by one or more fluoro; eachR^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆ alkyl,C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by one or morefluoro; and each p and q independently represents 1 or 2, with theprovisos that the compound of formula I does not represent: (A)2-((1-chloropropan-2-yl)sulfonyl)-6-methoxy-3-nitropyridine,2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethane-1-sulfonamide,2-((2-chloroethyl)sulfonyl)-6-methoxy-3-nitropyridine,2((4-chlorobutan-2-yl)sulfonyl)-6-methoxy-3-nitropyridine,2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)ethane-1-sulfonyl chloride,2-((3-chloro-2-methylpropyl)sulfonyl)-6-methoxy-3-nitropyridine,2-((3-chloropropyl)sulfonyl)-6-methoxy-3-nitropyridine,6-methoxy-3-nitro-2-(vinyl sulfonyl)pyridine, 6-methoxy-2-(methylsulfonyl)-3-nitropyridine,6-(2,6-dichloro-4-(trifluoromethyl)phenoxy)-2-(methylsulfonyl)-3-nitropyridine,6-(2,6-dichloro-4-(trifluoromethoxy)phenoxy)-2-(methylsulfonyl)-3-nitropyridine,or6-(2,6-dichloro-4-(trifluoromethyl)phenoxy)-2-(ethylsulfonyl)-3-nitropyridine;or (B) 2-(butylsulfinyl)-3-nitro-pyridine; or (C)3-[(3-nitro-2-pyridinyl)sulfinyl]-2-propenoic acid methyl ester,3-[(3-nitro-2-pyridinyl)sulfinyl]-2-propenoic acid ethyl ester,6-[(2-methylpropyl)sulfinyl]-5-nitro-2-methanesulfonate-2-pyridinol,3-chloro-2-[(6-chloro-3-nitro-2-pyridinyl)sulfinyl]-benzoic acid ethylester, 3-nitro-2-[(4-piperidinylmethyl)sulfinyl]-pyridine,3-nitro-2-[(3-pyrrolidinylmethyl)sulfinyl]-pyridine,3-nitro-2-[(3-piperidinylmethyl)sulfinyl]-pyridine,3-nitro-2-[(2-pyrrolidinylmethyl)sulfinyl]-pyridine,3-nitro-2-[(2-piperidinylmethyl)sulfinyl]-pyridine,4-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic acid1,1-dimethylethyl ester,3-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic acid1,1-dimethylethyl ester,3-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-pyrrolidinecarboxylic acid,1,1-dimethylethyl ester,2-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-pyrrolidinecarboxylic acid1,1-dimethylethyl ester,2-[[(3-nitro-2-pyridinyl)sulfinyl]methyl]-1-piperidinecarboxylic acid1,1-dimethylethyl ester,6-[2,6-dichloro-4-(trifluoromethoxy)phenoxy]-2-(methylsulfinyl)-3-nitro-pyridine,or6-[2,6-dichloro-4-(trifluoromethyl)phenoxy]-2-(ethylsulfinyl)-3-nitro-pyridine.2. A compound as claimed in claim 1, wherein X represents C₁₋₈ alkyl,C₂₋₈ alkenyl or C₂₋₈ alkynyl.
 3. A compound as claimed in claim 1,wherein when X represents C¹ alkyl X is substituted with at least one Ygroup.
 4. A compound as claimed in claim 1, wherein each Y independentlyrepresents halo, R^(a3), —CN, —C(O)N(R^(c3))R^(d3),—N(R^(p3))C(O)R^(b3), —C(O)OR^(e3), —N(R^(j3))R^(k3), —OR^(l3), —SR^(m3)or ═O.
 5. A compound as claimed in claim 1, wherein each Y independentlyrepresents halo, R^(a3), —C(O)N(R^(c3))R^(d3), —N(H)C(O)R^(b3),—C(O)OR^(e3), —N(R^(j3))R^(k3) or —OR^(l3).
 6. A compound as claimed inclaim 1, wherein: R¹ represents halo, —N(R^(j1))R^(k1), —OR^(l1) or—SR^(m1); and/or R² and R³ each independently represent H, halo, R^(a1),—N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1).
 7. A compound as claimed inclaim 1, wherein each R^(a1), R^(h1), R^(k1), R^(l1) and R^(m1)independently represent C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl eachoptionally substituted by one or more fluoro.
 8. A compound as claimedin claim 1, wherein: R¹ represents halo, —N(R^(j1))R^(k1) or —OR^(l1);and/or R² and R³ each independently represent H, halo, R^(a1),—N(R^(j1))R^(k1) or —OR^(l1).
 9. A compound as claimed in claim 1,wherein each R^(a1), R^(j1), R^(k1), R^(l1) and R^(m1) independentlyrepresent C₁₋₆ alkyl optionally substituted by one or more fluoro.
 10. Acompound as claimed in claim 1, wherein: R¹ represents halo,—N(R^(j1))R^(k1) or —OR^(l1); R² and R³ each independently represent H,halo (e.g. chloro), —N(R^(j1))R^(k1) or —OR^(l1); each R^(l1)independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g.C₁₋₆ alkyl) optionally substituted by one or more fluoro (such asmethyl, difluoromethyl, trifluoromethyl group); and/or (e.g. and) eachand R^(k1) independently represent C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl (e.g. C₁₋₆ alkyl) optionally substituted by one or more fluoro(such as a methyl group).
 11. A compound as claimed in claim 1, whereinR¹ represents a group other than H.
 12. A compound as claimed in claim1, wherein: R² and R³ represent H; and/or R¹ represents halo, —N(CH₃)₂or —OCH₃. 13-15. (canceled)
 16. A method of treating cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 1 but without provisos (A) and(C).
 17. The method of claim 16, wherein the cancer is selected from thegroup consisting of: soft tissue cancers, such as sarcoma, myxoma,rhabdomyoma, fibroma, lipoma and teratoma; lung cancers, such asbronchogenic carcinoma, alveolar or bronchiolar carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;gastrointestinal cancers: such as esophageal cancers, stomach cancers,pancreatic cancers, small bowel cancers, large bowel cancers;genitourinary tract cancers, such as cancer of the kidney, bladder andurethra, prostate, testis; liver cancers, such as hepatoma,cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma; bone cancers, such as osteogenic sarcoma,fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma, multiple myeloma, malignant giant celltumor chordoma, osteochronfroma, benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors; cancers ofthe head and/or nervous system, such as cancer of the skull, meninges,brain, spinal cord; gynecological cancers, such as cancers of theuterus, cervix, ovaries, cancers of the vulva, vagina, fallopian tubes;haematologic cancers, such as cancers of the blood and bone marrow,Hodgkin's disease, non-Hodgkin's lymphoma; skin cancers, such asmalignant melanoma, basal cell carcinoma, squamous cell carcinoma,Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids; neurofibromatosis and adrenal glands; andneuroblastomas.
 18. The method of claim 16, wherein the cancer is asolid tumor cancer.
 19. A pharmaceutical composition comprising acompound as defined in claim 1 but without provisos (A) and (C), andoptionally one or more pharmaceutically acceptable adjuvant, diluentand/or carrier.
 20. A combination product comprising: (A) a compound asdefined in claim 1 but without provisos (A) and (C); and (B) one or moreother therapeutic agent that is useful in the treatment of cancer,wherein each of components (A) and (B) is formulated in admixture,optionally with one or more a pharmaceutically-acceptable adjuvant,diluent or carrier.
 21. A kit-of-parts comprising: (a) a pharmaceuticalformulation as defined in claim 19; and (b) one or more othertherapeutic agent that is useful in the treatment of cancer, optionallyin admixture with one or more pharmaceutically-acceptable adjuvant,diluent or carrier, which components (a) and (b) are each provided in aform that is suitable for administration in conjunction with the other.22. A process for the preparation of a compound as defined in claim 1,which process comprises: (i) where n represents 2, reaction of acompound of formula IIA

wherein R¹, R² and R³ are as defined in claim 1 and LG¹ represents asuitable leaving group, with a compound of formula IIIA

wherein X is as defined in claim 1 and M represents an alkali metal ion,in the presence of a suitable acid and in the presence of a suitablesolvent, and optionally in the presence of a suitable phase transfercatalyst; (ii) where n represents 2, reaction of a compound of formulaIIB

wherein R¹, R² and R³ are as defined in claim 1 and M represents analkali metal ion, with a compound of formula TIM

wherein X is as defined in claim 1 and LG² represents a suitable leavinggroup, in the presence of a suitable acid and in the presence of asuitable solvent, and optionally in the presence of a suitable phasetransfer catalyst; (iii) where n represents 2, reaction of a compound offormula IIA with a compound of formula IIIA, in the presence of asuitable metal halide and in the presence of a suitable solvent; (iv)where n represents 2, reaction of a compound of formula IIB with acompound of formula IIIB, in the presence of a suitable metal halide andin the presence of a suitable solvent; (v) reaction of a compound offormula IV

wherein R¹ to R³ and X are as defined in claim 1, with a suitableoxidising agent in the presence of a suitable solvent, and optionally inthe presence of water; (vi) where n represents 2, reaction of a compoundof formula V

wherein R¹, R² and R³ are as defined in claim 1 and LG³ represents asuitable leaving group with a compound of formula VI

wherein X is as defined in claim 1, in the presence of a suitable Lewisacid and in the presence of a suitable solvent.
 23. (canceled)